Next Article in Journal
Analysis of Risk Factors for Phonation Disorders after Thyroid Surgery
Next Article in Special Issue
Cellular Models of Alpha-Synuclein Aggregation: What Have We Learned and Implications for Future Study
Previous Article in Journal
Fertility Preservation and Reproductive Potential in Transgender and Gender Fluid Population
Previous Article in Special Issue
Sex-Related Differences in Voluntary Alcohol Intake and mRNA Coding for Synucleins in the Brain of Adult Rats Prenatally Exposed to Alcohol
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Biomedicines
Volume 10
Issue 9
10.3390/biomedicines10092278
biomedicines-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Synuclein Proteins in MPTP-Induced Death of Substantia Nigra Pars Compacta Dopaminergic Neurons

by
Valeria V. Goloborshcheva
1,*,
Valerian G. Kucheryanu
1,
Natalia A. Voronina
1,
Ekaterina V. Teterina
2,
Aleksey A. Ustyugov
2 and
Sergei G. Morozov
1
1
Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia
2
Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Russia
*
Author to whom correspondence should be addressed.
Biomedicines 2022, 10(9), 2278; https://doi.org/10.3390/biomedicines10092278
Submission received: 30 July 2022 / Revised: 1 September 2022 / Accepted: 6 September 2022 / Published: 14 September 2022
(This article belongs to the Special Issue Recent Advances in Understanding of the Role of Synuclein Family Members in Health and Disease)
Browse Figure
Versions Notes

Abstract

:
Parkinson’s disease (PD) is one of the key neurodegenerative disorders caused by a dopamine deficiency in the striatum due to the death of dopaminergic (DA) neurons of the substantia nigra pars compacta. The initially discovered A53T mutation in the alpha-synuclein gene was linked to the formation of cytotoxic aggregates: Lewy bodies in the DA neurons of PD patients. Further research has contributed to the discovery of beta- and gamma-synucleins, which presumably compensate for the functional loss of either member of the synuclein family. Here, we review research from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity models and various synuclein-knockout animals. We conclude that the differences in the sensitivity of the synuclein-knockout animals compared with the MPTP neurotoxin are due to the ontogenetic selection of early neurons followed by a compensatory effect of beta-synuclein, which optimizes dopamine capture in the synapses. Triple-knockout synuclein studies have confirmed the higher sensitivity of DA neurons to the toxic effects of MPTP. Nonetheless, beta-synuclein could modulate the alpha-synuclein function, preventing its aggregation and loss of function. Overall, the use of knockout animals has helped to solve the riddle of synuclein functions, and these proteins could be promising molecular targets for the development of therapies that are aimed at optimizing the synaptic function of dopaminergic neurons.

1. Introduction

The synuclein family consists of three highly homologous genes encoding proteins similar in structure: alpha-, beta-, and gamma-synuclein. Among the three representatives of the synuclein family, alpha-synuclein is the best-studied and the volume of scientific research devoted to its functions significantly exceeds the much-needed attention to the other two members altogether [1]. Despite extensive international studies of the synuclein family of proteins, their physiological functions as well as their pathophysiological role in synuclein-associated neurodegenerative diseases have not been fully resolved [2]. The question remains open whether the formation of Lewy bodies is the primary cause of Parkinson’s disease (PD) or whether it is a by-product of the activation of intracellular defense mechanisms against the ongoing debilitating neurodegenerative process.
In order to understand these fundamental questions, modern experimental science is developing new hybrid forms of parkinsonism in laboratory model animal systems. A toxic PD model that was initiated by single or multiple treatments of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was actively used in knockout animals lacking one or more synucleins as well as in mice overexpressing a mutant form of the human protein [3,4,5,6,7]. In this review, we focus on current findings on the potential role of the synuclein family of proteins during the MPTP-induced death of substantia nigra pars compacta (SNpc) dopaminergic neurons (DA neurons) of the midbrain.

2. Synuclein Structure and Functions

Synucleins are a family of small soluble proteins that have at least five amino acid repeats located in the N-terminal region, resulting in an alpha-helical conformation with the C-terminal region remaining unstructured [8,9,10]. In contrast to alpha-synuclein, beta-synuclein does not contain the internal hydrophobic region corresponding with the non-beta-amyloid component (NAC) peptide, which makes alpha-synuclein capable of forming aggregates [11]. The alpha-synuclein protein was first detected in the Torpedo California electric scat in 1988 [12], but was later identified as a precursor protein in the amyloid plaques of Alzheimer’s disease patients [13]. Somewhat later, beta-synuclein was isolated from the presynaptic endings of rat and bovine brains [14,15]; gamma-synuclein was found in breast cancer metastases [16], but was further isolated from the mouse trigeminal nerve [17].
All synucleins are actively expressed in nervous system tissues. High expression levels in the neocortex, hippocampus, striatum, and cerebellum are typical for alpha- and beta-synuclein [18], but, in addition to the CNS, these proteins can also be found in blood cells, astrocytes, skeletal muscles, and the liver [11,19,20]. The first two proteins are highly represented in many structures of the brain and their levels in the spinal cord and peripheral nervous system are relatively low; the opposite is found for gamma-synuclein, with a high expression level in the motor neurons of the spinal cord and medulla oblongata, neurons of the sympathetic and parasympathetic peripheral nervous system, tumor entities, and retinal ganglion cells [9,21].
Despite independent roles in the cell, synucleins are highly homologous and have similar functions, often compensating for the dysfunction between each other. Synucleins are important for the synaptic transmission and circulation of synaptic vesicles [22,23,24,25,26,27]. Alpha-synuclein modulates the release of neurotransmitters from presynaptic terminals by binding and clustering synaptic vesicles and chaperoning the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly by binding to the protein synaptobrevin-2 (VAMP2) [28,29] whereas beta-synuclein and gamma-synuclein modulate the synaptic vesicular binding of alpha-synuclein and thus reduce the synaptic physiological activity of alpha-synuclein [30,31] (Table 1). Moreover, in vitro and in vivo experiments have revealed that all three members of the synuclein family have chaperone activity [32,33,34].
Alpha-, beta-, and gamma-synucleins can bind to the dopamine transporter (DAT) and modulate its delivery to the synaptic membrane, thereby affecting dopamine neurotransmitter reuptake [11,31,35]. In turn, it has been shown through protein–protein interactions that alpha-synuclein can affect DAT activity and this effect is regulated by the gamma-synuclein concentration [36,37,38]. Alpha-synuclein is involved in maintaining the required level of dopamine (DA) and if its function cannot be performed due to a mutation, a vesicle degradation occurs [27]. The mechanism of this effect has multiple roots: alpha-synuclein regulates synaptic DA homeostasis [39], affects the expression of DA synthesis member genes (such as GTP-cyclohydrolase, tyrosine hydroxylase (TH), and aromatic acid decarboxylase) [40], modulates synaptic DA reuptake by binding to DAT [41], and inhibits DA release in response to repeated excitation [42,43]. Previously, there was no evidence for an interaction between beta-synuclein and TH, but it has been suggested that it may functionally overlap with alpha-synuclein [44]. Moreover, a recent study convincingly demonstrated that beta-synuclein potentiates vesicular dopamine uptake, presumably by the assembly of the TH/AADC/VMAT-2 protein complex, which is probably not functionally compensated by alpha- or gamma-synuclein [4].
Synucleins are also lipid-binding proteins capable of inducing membrane curvature and turning large vesicles into highly curved formations [11,31,45]. Moreover, gamma-synuclein regulates lipid metabolism in adipocytes and the lack of this protein has a significant impact on the energy metabolism of the whole organism [46]. In addition, alpha- and beta-synucleins prevent cell autolysis. For example, beta-synuclein possesses p53-dependent anti-apoptosis properties at low physiological concentrations, inhibiting caspase-3 activation by binding to Akt [47,48].
A number of studies have found that alpha-synuclein is able to bind to the mitochondria and even penetrate them through VDAC channels (the outer membrane metabolic channel), thus probably targeting the mitochondrial respiratory chain complexes in the inner membrane [49,50,51], but the physiological significance of this interaction remains unclear. A difference in the lipid composition of the mitochondrial membrane is a regulatory link in the affinity with the alpha-synuclein–VDAC interaction [52].
Beta-synuclein binds to metals to regulate cellular metal homeostasis, particularly chelated copper ions, which can produce free radicals and promote the formation of cytotoxic alpha-synuclein oligomers [11,53,54]. There is also a suggestion that beta-synuclein can affect the autophagic–lysosomal pathway, removing damaged or toxic protein molecules and even aggregates [55,56]. In turn, gamma-synuclein optimizes the autophagy process, which protects colon cancer cells from endoplasmic reticulum stress [57].
The ubiquitin–proteasome system that provides controlled protein degradation is extremely important for the removal of toxic oligomers and soluble protofibrillar structures formed by proteins prone to aggregation, including synucleins. All three members of the synuclein family are able to interact with proteasomes but with different efficiencies. For alpha-synuclein, the interaction depends on the degree of its aggregation [58,59]. Monomeric beta-synuclein also has a low inhibitory effect on 20S and 26S proteasome complexes, but monomeric gamma-synuclein inhibits ubiquitin-independent proteolysis much more effectively. Interestingly, beta-synuclein acts as a negative regulator of alpha-synuclein in these processes [60].
Gamma-synuclein is involved in the stabilization of the cell cytoskeleton [61]. Although alpha-synuclein is capable of interacting with a few components of the cytoskeleton—in particular, with tubulin—the putative effects of alpha-synuclein on its polymerization are not clear [62]. In the lysates of cancer cells, gamma-synuclein was found both in the cytosolic fraction and in the cytoskeleton fraction and the role of gamma-synuclein in stabilizing the neurofilament network in neurons was also revealed [63].
Interestingly, several studies have shown a modulating role of alpha-synuclein in the formation of populations of the SNpc DA neurons of the midbrain. Alpha-synuclein takes part in the maturation of SNpc DA neurons whilst the development of the adjacent similar anatomical structure, the ventral tegmental area (VTA), proceeds independently [64]. In turn, one of the possible roles of synucleins is considered to be participation in the regeneration of damaged neural tissues. It was found that the concentration of alpha- and beta-synucleins (gamma-synuclein-less) was significantly increased around damaged neural endings [65,66]. Hence, the link between synucleins and neurodegeneration can be explained not only by pathological aggregation and its induced toxicity, but also by the loss of normal function. Disruptions in the structure, intracellular localization, and compartmentalization of the synuclein family of proteins result in pathological conditions called synucleinopathies.

3. Parkinson’s Disease Is a Form of Synucleinopathy

Parkinsonian syndrome (or parkinsonism) is a neurological condition with a multifactorial etiology caused by a disorder in the extrapyramidal system of the brain. Parkinsonism is clinically characterized by a triad of signs (bradykinesia, rigidity, and tremor) and it has additional motor and non-motor pathological manifestations. The debut of the disease usually occurs between the ages of 65 and 70, with less than 5% of cases in patients younger than 45 [67,68].
According to worldwide statistics, the prevalence of parkinsonism in the general population ranges from 100 to 200 cases per 100,000 people, with an annual increase of 15 cases per 100,000 people [69]. In reality, these figures are underestimated due to the low detection rate at the initial stages of the disease and difficulties in the differential diagnosis of various extrapyramidal pathologies burdened with a PD-like set of symptoms.
Parkinson’s disease (PD) is the most common form of parkinsonian syndrome and it is etiopathogenetically designated as primary or idiopathic parkinsonism. However, there are other clinical forms of neurodegenerative diseases to be considered. These include progressive supranuclear palsy (Steele–Richardson–Olszewski syndrome), Huntington’s chorea, and corticobasal degeneration (CBD) as well as secondary drug-induced toxic parkinsonism and many others [70,71]. These diseases can be differentiated on the basis of key clinical features as well as a clear understanding of the pathogenetic mechanisms underlying PD, which is crucial for the diagnosis, treatment, and prognosis of the neurodegenerative process in the extrapyramidal system.
Pathophysiologically, PD is characterized by the degeneration of dopaminergic neurons in the substantia nigra of the midbrain due to the cytotoxic aggregation and formation of cytoplasmic inclusions—Lewy bodies (LBs)—resulting in a dopamine deficiency in the striatum and in other associated structures of the basal ganglia [72,73,74]. LBs contain aggregated forms of the alpha-synuclein protein, which is also present in other neurodegenerative disorders, including multiple system atrophy, dementia with Lewy bodies [75,76], Hallervorden–Spatz disease, and many others that are collectively referred to as “synucleinopathies” [77]. Although a small percentage of patients with PD have a monogenic form of the disease (LRRK2, parkin, etc.), in most cases the disorder is sporadic with an unknown etiology. Normally, alpha-synuclein is present in several states, such as monomeric, dimeric, oligomeric, and fibrillar forms. However, alpha-synuclein oligomers exert the most toxic effects on DA neurons [78]. An increased concentration of alpha-synuclein oligomers was found in the substantia nigra [79,80], cerebrospinal fluid [81], and blood [82] of PD patients. The intranasal administration of oligomeric forms of alpha-synuclein to C57BL/6J mice caused PD-like symptoms [83]. These data all suggest that the oligomeric form of alpha-synuclein has a pathogenetic significance in the development of PD. However, the exact mechanisms of the involvement of alpha-synuclein oligomers in the death of nigrostriatal dopaminergic neurons are currently unknown.
A joint injection of MPTP and alpha-synuclein oligomers into the striatum of C57BL/6J mice resulted in the activation of astrocytes and microglia in the substantia nigra and increased the loss of nigral TH+ neurons and the development of motor deficits in animals to a greater extent than MPTP-only treatments. These results indicate that alpha-synuclein oligomerization induces a neurotoxic effect on DA neurons in SN [6]. Activated microglia secrete proinflammatory cytokines IL-1β, IL-6, IL-10, interferon gamma (IFN-γ), and tumor necrosis factor-α (TNF-α). These secretions activate the nuclear transcription factor NF-kB, triggering core apoptosis and inducible NO synthase (iNOS), leading NO and other ROS and cyclooxygenase-2 (COX2) to increase the formation of prostaglandin E2. The presence of these pathogenic factors eventually causes the death of SNpc DA neurons [84]. Thus, it is crucial to use various models of parkinsonism—including laboratory animals such as transgenic mice with an overexpression of a mutant form of human alpha-synuclein (A53T; A30P), toxin-induced models (6-hydroxydopamine (6-OHDA), MPTP, and reserpine), and knockout mice lines with a depletion of Parkin/Park genes (Pink-1, DJ-1, and synuclein family proteins)—in order to fully understand the mechanisms of PD pathogenesis.

3.1. Toxic Animal Modeling of Parkinsonism Using MPTP

The toxic modeling of parkinsonism with MPTP was proposed at the end of the 20th century. Dr. Langston discovered clinical PD symptoms in addicts of “synthetic heroin”, which contained MPTP as one of its byproducts [85]. The discovery of MPTP-induced parkinsonian syndrome provoked a number of scientific studies worldwide that were aimed at determining the pathophysiological mechanisms underlying parkinsonism and it raised the disciplines of neurochemistry and neurobiology to a new level. Thus, MPTP was found to cause the extensive selective death of dopaminergic neurons in the substantia nigra [86]. The results of biochemical studies and an analysis of the cytoarchitectonics of SNpc revealed a decrease in the dopamine content in the striatum and a decrease in the number of nigrostriatal DA neurons in various MPTP-treated animals, including monkeys [87], dogs [88], cats [89], mice [64], and even frogs [90]. A local neurodegeneration caused by a single injection of MPTP at relatively low doses (5–10 mg/kg for dogs and cats; 30 mg/kg for mice) resulted in symptoms (hypokinesia, muscle rigidity, and tremor) that were typical for idiopathic parkinsonism. Yet, not all laboratory animals are sensitive to MPTP. For example, rats, rabbits, and guinea pigs required relatively high doses of MPTP (50–70 mg/kg) in order to manifest the neurological signs of an extrapyramidal system dysfunction, which leads to the development of parkinsonism [91].
MPTP is a lipophilic compound that freely crosses the blood–brain barrier and is metabolized by MAO-B in the glial cells to 1-methyl-4-phenylpyridine in an ionic form (MPP+), which is a highly toxic final metabolite [85,92]. DA neurons in the SNpc then selectively capture MPP+ from the intercellular space using the membrane transporter DAT due to its structural similarities to the dopamine molecule [93]. MPP+ accumulates in the mitochondria where it inhibits complex I of the electron transport chain, leading to the inhibition of cellular respiration [94,95], decreased ATP production [96,97], oxidative stress [98,99], the activation of the caspase cascade [100], and, ultimately, cell death.
The MPTP-toxic model of parkinsonism induced in C57BL/6J mice is widely accepted as the primary system to study the pathogenetic mechanisms that underlie extrapyramidal system disorders and that contribute to PD as well as to develop prospective neuroprotection strategies. Over the past decades, numerous protocols have been created to model toxic parkinsonism. These protocols are grouped based on the speed and severity of the clinical signs into three main categories: “acute administration” (several MPTP doses in one day); “subchronic administration” (usually 1–2 doses a day for a 5-day period); and “chronic” administration (multiple injections for 1 month or more) [101,102].
As indicated earlier, synuclein family proteins are actively involved in the processes of dopamine neurotransmission in the presynaptic endings of SNpc DA neurons. The saturation of the presynaptic endings of DA neurons with the toxic end-metabolite of MPTP—1-methyl-4-phenylpyridine in an ionic form (MPP+), which has a high affinity with the plasma membrane transporter DAT—is presumably directly related to the activity of synuclein family proteins (Figure 1). Thus, the selective pathological effect of MPP+ is based on the ability of neurons to reuptake the neurotransmitter from the synaptic cleft in order to replenish the intracellular stores and form new vesicles [103] where synucleins could play a special role.

3.2. Synucleins and MPTP Toxicity

Dopamine is the most important signaling neurotransmitter that regulates the motor function of the entire extrapyramidal system, which is responsible for the superstructure of movements [104]. MPP+ is structurally similar to dopamine and it competes for binding sites on the presynaptic membrane of DA neurons. In toxic conditions, such as parkinsonism, DA neurons are particularly sensitive and vulnerable to the pathological effects of MPP+, which entails a series of dramatic events leading to the complete degeneration of the nigrostriatal pathway because DA neuron bodies lie in the substantia nigra of the midbrain with axons extending to the dorsal striatum. On the other hand, it is not quite clear what role synuclein family proteins play in these processes as the main representative of the family, alpha-synuclein, acts as a pathological marker of PD.
The first and subsequent studies on the effects of MPTP toxicity in alpha-synuclein-deficient animals showed surprising results: acute and chronic neurotoxin administration protocols did not have the desired effect on the death of the DA neurons of the SNpc despite lower cell counts [105,106,107,108] (Table 2). Moreover, several in vitro studies demonstrated that an overexpression of human alpha-synuclein was associated with enhanced cell death after MPP+ exposure [109,110]. MPTP administration to mice with a selective inactivation of alpha-synuclein in a few cases resulted in a dopamine deficiency and the manifestation of early clinical symptoms of a dopaminergic system dysfunction typical of the early stages of PD [7], which indirectly indicated the activation of the compensatory mechanisms of DA/MPP+ neurotransmission. It is worth emphasizing that phenotypically alpha-synuclein-knockout mice do not differ from wild-type animals [111,112]. However, decreased levels of striatal dopamine in a few lines [113,114] resulted in a reduced availability of DAT on neuronal surfaces [107] and the early debut of Parkinson-like symptoms in aging mice [114,115,116]. Although neurons manage to compensate for a lack of alpha-synuclein, this takes a toll on the restructuring of the defense systems, which, under certain conditions, can lead to the development of pathological processes, primarily in those cellular compartments where alpha-synuclein normally functions.
In turn, animals with a gamma-synuclein deficiency showed a similar response to MPTP-induced dopaminergic neurodegeneration. Here, the main feature was also the resistance of SNpc DA neurons to the toxic effect of MPTP [5,113,116]. Notably, a comparative immunoblotting analysis of the synuclein levels in the midbrain of gamma- and alpha-synuclein-knockout vs. wild-type mice showed increased levels of beta-synuclein [5,117]. This phenomenon led to a further strategy to investigate the role of synucleins in the development of MPTP resistance.
Recent studies have convincingly demonstrated that beta-synuclein is involved in optimizing the capture of dopamine and probably that of structurally similar molecules via VMAT-2 (vesicular monoamine transporter-2) [4]. Moreover, there was a loss of resistance of the DA neurons in the SNpc to MPP+, which is a toxic metabolite of MPTP, in beta-synuclein knockouts. A similar effect was observed in triple-knockout mice (triple synuclein-deficient mice), where the initial population of DA neurons in the SNpc was similar to wild-type mice [4]. In cases of alpha- and/or gamma-synuclein deficiency there was a 2.8-fold increase in the VMAT-2 density per vesicle [107], probably due to the increased presence of beta-synuclein at the presynaptic end, which was consistent with other studies [5]. However, DA neurons in the SNpc are known to be particularly susceptible to MPP+ because they have a higher DAT/VMAT-2 ratio than other brain neurons [11]. Thus, a reduced DAT transporter in the presynapse, combined with an increased VMAT-2 density in the vesicles, changed the VMAT-2/DAT ratio, leading to the utilization of toxic MPP+ molecules. Taken together, these results suggest a direct involvement of beta-synuclein in the developmental processes of the resistance of SNpc DA neurons to neurotoxins rather than the absence of alpha- or gamma-synucleins per se.
The potential neuroprotective properties of beta-synuclein also include the regulation of cellular apoptosis. Serine threonine kinase (Akt) is an enzyme that inhibits apoptosis by phosphorylating the Mdm2 protein that binds to p53 in the nucleus. In an experiment by Hashimoto et al., it was shown that a beta-synuclein overexpression in a rat neuroblastoma B103 cell line resulted in the resistance of these cells to the toxic action of rotenone, which, in a similar manner to MPTP, inhibits mitochondrial respiratory chain complex I. However, an Akt inhibition in this cell line resulted in the loss of neuronal resistance to neurotoxin exposure [118].
The specific damaging effect of MPTP on catecholaminergic neurons is also associated with the activation of toxic A-astrocytes, which, under the influence of proinflammatory mediators, inhibit the glutamate capture via GLT-1 and induce the production of inflammatory cytokines, leading to neuroinflammation [119]. Moreover, a disruption of the Nrf2 system in astrocytes leads to a decrease in the number of antioxidant molecules, resulting in oxidative stress. Damaged DA neurons secrete oligomeric alpha-synuclein in PD. The transfer of alpha-synuclein from neurons to astrocytes, with the subsequent accumulation and deposition in astrocytes, leads to the formation of proinflammatory cytokines and the disruption of the glutamate capture via GLT-1 [119]. Such a scenario is possible in the case of a long-term protocol of chronic MPTP administration, for which the presence of amyloid-like inclusions in both the astrocytes and DA neurons in the SNpc has been noted [120,121].
An abnormal aggregation of alpha-synuclein can increase the degree of glutamate excitotoxicity. Alpha-synuclein accumulation in astrocytes affects the glutamate transport, causing increased extracellular glutamate concentrations and excitotoxicity, further aggravating the damage to the dopaminergic neurons [122]. These data emphasize that alpha-synuclein increases the glutamate release. The concentration of alpha-synuclein itself depends on the release of activity-dependent presynaptic glutamate from the endings of the forebrain neurons [123]. In addition, the overexpression of alpha-synuclein increases the phosphorylation of N-methyl-D-aspartate (NMDA) receptors, thereby increasing the formation of NR1 and NR2B subunits and the sensitivity of NMDA receptors to developing glutamate excitotoxicity [124]. Increased levels of glutamate in the intercellular space activates glutamate NMDA receptors, leading to a calcium overload and the death of DA neurons [125,126,127]. Alpha-synuclein can also enhance glutamate excitotoxicity by accelerating α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor signaling [128].
The formation of reactive oxygen species (ROS) is directly involved in the pathogenesis of MPTP-induced parkinsonism [103]. It is unclear how synuclein family proteins are related to these events. It has been established that an alpha-synuclein deficiency leads to the inhibition of nitric oxide synthase (NOS), which forms another powerful oxidant, peroxynitrite (ONOO−), by interacting with ROS [107]. Thus, NOS activation is an important step in MPTP-induced toxicity and it can be inhibited by a targeted inactivation of alpha-synuclein. Therefore, this targeted inactivation could be a promising direction for the development of a PD therapy.
Finally, there is an assumption that alpha-synuclein specifically interacts with the mitochondria by blocking the toxic effect of neurotoxins, which have an established pathogenic action on DA neurons, leading to the development of PD [129,130]. However, this protective function of synucleins does not extend to all cells; in particular, not to differentiated DA neurons. This may imply that the cytoprotective properties of alpha-synuclein are aimed at optimizing the mitochondrial function and directly depend on the stage of cell differentiation; i.e., are linked to aging [27]. This is indirectly confirmed by studies of the role of alpha-synuclein in the maturation of SNpc DA neurons in the early postnatal developmental period [64].

4. Concluding Remarks and Future Directions

All proteins of the synuclein family are distributed throughout the nervous system, predominantly performing the optimization and systematization functions of various processes. Based on all the studies summarized in this review, we conclude that the differences in the sensitivity of synuclein-knockout animals compared with MPTP neurotoxin models are due to and result from the ontogenetic selection of early neurons followed by a compensatory effect of beta-synuclein, which optimizes the DA capture in the synapses. This is supported by MPTP toxicity data from synuclein-free animals with the inactivation of all three members. Compared with single alpha- or gamma-synuclein knockouts, the sensitivity of DA neurons to the toxic effects of MPTP is higher in triple-knockout animals and almost identical to the levels shown in wild-type controls, suggesting that beta-synuclein could modulate the alpha-synuclein function, preventing its aggregation and a loss of function. Thus, synucleins can be considered to be promising molecular targets for the development of therapies that are aimed at optimizing the synaptic function of dopaminergic neurons. Knockout mice lacking any of the three synuclein members could be used as a promising tool to study the mechanisms of the neurodegenerative processes of synucleinopathies such as PD.

Author Contributions

V.V.G. drafted the work; V.G.K. helped in writing the manuscript and approved the submitted version; N.A.V. and E.V.T. reviewed the literature; A.A.U. contributed to the conception or design of the work, and S.G.M. substantively revised it and approved the submitted version. All authors have read and agreed to the published version of the manuscript.

Funding

The work is supported by grant agreement No. 075-15-2020-795 and state contract No. 13.1902.21.0027 of 29.09.2020 unique project ID: RF-190220X0027.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We would like to thank Claire McQuerry for valuable comments and for proof-reading the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

PDParkinson’s disease
DADopamine
NF-kBNuclear factor kappa-light-chain-enhancer of activated B cells
DA neuronsDopaminergic neurons
MPTP1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
MPP+1-methyl-4-phenylpyridine in ionic form
SNpcSubstantia nigra pars compacta
NACNon-beta-amyloid component
CNSCentral nervous system
SNARESoluble N-ethylmaleimide-sensitive factor attachment protein receptor
VAMP-2Protein synaptobrevin-2
VMAT-2Vesicular monoamine transporter-2
DATDopamine transporter
THTyrosine hydroxylase
VDACVoltage-dependent anion channels
VTAVentral tegmental area
CBDCorticobasal degeneration
IL-1βInterleukin-1β
IL-6Interleukin-6
IL-10Interleukin-10
IFN-γInterferon gamma
TNF-αTumor necrosis factor-α
MAO-BMonoamine oxidase B
iNOSInducible NO synthase
NONitric oxide
ONOOPeroxynitrite
COX2Cyclooxygenase-2 enzyme
NMDAN-methyl-D-aspartate
AMPAα-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
ROSReactive oxygen species

References

  1. Bras, J.; Gibbons, E.; Guerreiro, R. Genetics of synucleins in neurodegenerative diseases. Acta Neuropathol. 2021, 141, 471–490. [Google Scholar] [CrossRef]
  2. Mahoney-Sanchez, L.; Bouchaoui, H.; Ayton, S.; Devos, D.; Duce, J.A.; Devedjian, J.C. Ferroptosis and its potential role in the physiopathology of Parkinson’s Disease. Prog. Neurobiol. 2021, 196, 101890. [Google Scholar] [CrossRef]
  3. Schluter, O.M.; Fornai, F.; Alessandri, M.G.; Takamori, S.; Geppert, M.; Jahn, R.; Sudhof, T.C. Role of alpha-synuclein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice. Neuroscience 2003, 118, 985–1002. [Google Scholar] [CrossRef]
  4. Ninkina, N.; Millership, S.J.; Peters, O.M.; Connor-Robson, N.; Chaprov, K.; Kopylov, A.T.; Montoya, A.; Kramer, H.; Withers, D.J.; Buchman, V.L. Beta-synuclein potentiates synaptic vesicle dopamine uptake and rescues dopaminergic neurons from MPTP-induced death in the absence of other synucleins. J. Biol. Chem. 2021, 297, 101375. [Google Scholar] [CrossRef]
  5. Robertson, D.C.; Schmidt, O.; Ninkina, N.; Jones, P.A.; Sharkey, J.; Buchman, V.L. Developmental loss and resistance to MPTP toxicity of dopaminergic neurones in substantia nigra pars compacta of gamma-synuclein, alpha-synuclein and double alpha/gamma-synuclein null mutant mice. J. Neurochem. 2004, 89, 1126–1136. [Google Scholar] [CrossRef]
  6. Merghani, M.M.; Ardah, M.T.; Al Shamsi, M.; Kitada, T.; Haque, M.E. Dose-related biphasic effect of the Parkinson’s disease neurotoxin MPTP, on the spread, accumulation, and toxicity of alpha-synuclein. Neurotoxicology 2021, 84, 41–52. [Google Scholar] [CrossRef]
  7. Chaprov, K.D.; Teterina, E.V.; Roman, A.Y.; Ivanova, T.A.; Goloborshcheva, V.V.; Kucheryanu, V.G.; Morozov, S.G.; Lysikova, E.A.; Lytkina, O.A.; Koroleva, I.V.; et al. Comparative Analysis of MPTP Neurotoxicity in Mice with a Constitutive Knockout of the alpha-Synuclein Gene. Mol. Biol. 2021, 55, 152–163. [Google Scholar] [CrossRef]
  8. Patel, D.; Bordoni, B. Physiology, Synuclein; StatPearls Publishing: Treasure Island, FL, USA, 2022. [Google Scholar]
  9. Burre, J.; Sharma, M.; Sudhof, T.C. Cell Biology and Pathophysiology of alpha-Synuclein. Cold Spring Harb. Perspect Med. 2018, 8, a024091. [Google Scholar] [CrossRef]
  10. Carija, A.; Pinheiro, F.; Pujols, J.; Bras, I.C.; Lazaro, D.F.; Santambrogio, C.; Grandori, R.; Outeiro, T.F.; Navarro, S.; Ventura, S. Biasing the native alpha-synuclein conformational ensemble towards compact states abolishes aggregation and neurotoxicity. Redox Biol. 2019, 22, 101135. [Google Scholar] [CrossRef]
  11. Hayashi, J.; Carver, J.A. beta-Synuclein: An Enigmatic Protein with Diverse Functionality. Biomolecules 2022, 12, 142. [Google Scholar] [CrossRef]
  12. Maroteaux, L.; Campanelli, J.T.; Scheller, R.H. Synuclein: A neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J. Neurosci. 1988, 8, 2804–2815. [Google Scholar] [CrossRef] [PubMed]
  13. Ueda, K.; Fukushima, H.; Masliah, E.; Xia, Y.; Iwai, A.; Yoshimoto, M.; Otero, D.A.; Kondo, J.; Ihara, Y.; Saitoh, T. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc. Natl. Acad. Sci. USA 1993, 90, 11282–11286. [Google Scholar] [CrossRef]
  14. Nakajo, S.; Omata, K.; Aiuchi, T.; Shibayama, T.; Okahashi, I.; Ochiai, H.; Nakai, Y.; Nakaya, K.; Nakamura, Y. Purification and characterization of a novel brain-specific 14-kDa protein. J. Neurochem. 1990, 55, 2031–2038. [Google Scholar] [CrossRef]
  15. Tobe, T.; Nakajo, S.; Tanaka, A.; Mitoya, A.; Omata, K.; Nakaya, K.; Tomita, M.; Nakamura, Y. Cloning and characterization of the cDNA encoding a novel brain-specific 14-kDa protein. J. Neurochem. 1992, 59, 1624–1629. [Google Scholar] [CrossRef]
  16. Ji, H.; Liu, Y.E.; Jia, T.; Wang, M.; Liu, J.; Xiao, G.; Joseph, B.K.; Rosen, C.; Shi, Y.E. Identification of a breast cancer-specific gene, BCSG1, by direct differential cDNA sequencing. Cancer Res. 1997, 57, 759–764. [Google Scholar]
  17. Buchman, V.L.; Adu, J.; Pinon, L.G.; Ninkina, N.N.; Davies, A.M. Persyn, a member of the synuclein family, influences neurofilament network integrity. Nat. Neurosci. 1998, 1, 101–103. [Google Scholar] [CrossRef]
  18. Iwai, A.; Masliah, E.; Yoshimoto, M.; Ge, N.; Flanagan, L.; de Silva, H.A.; Kittel, A.; Saitoh, T. The precursor protein of non-A beta component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron 1995, 14, 467–475. [Google Scholar] [CrossRef]
  19. Jakes, R.; Spillantini, M.G.; Goedert, M. Identification of two distinct synucleins from human brain. FEBS Lett. 1994, 345, 27–32. [Google Scholar] [CrossRef]
  20. Tanji, K.; Mori, F.; Nakajo, S.; Imaizumi, T.; Yoshida, H.; Hirabayashi, T.; Yoshimoto, M.; Satoh, K.; Takahashi, H.; Wakabayashi, K. Expression of beta-synuclein in normal human astrocytes. Neuroreport 2001, 12, 2845–2848. [Google Scholar] [CrossRef]
  21. Le, T.; Winham, C.L.; Andromidas, F.; Silver, A.C.; Jellison, E.R.; Levesque, A.A.; Koob, A.O. Chimera RNA interference knockdown of gamma-synuclein in human cortical astrocytes results in mitotic catastrophe. Neural. Regen. Res. 2020, 15, 1894–1902. [Google Scholar] [CrossRef]
  22. Butler, B.; Sambo, D.; Khoshbouei, H. Alpha-synuclein modulates dopamine neurotransmission. J. Chem. Neuroanat. 2017, 83–84, 41–49. [Google Scholar] [CrossRef] [PubMed]
  23. Bernal-Conde, L.D.; Ramos-Acevedo, R.; Reyes-Hernandez, M.A.; Balbuena-Olvera, A.J.; Morales-Moreno, I.D.; Arguero-Sanchez, R.; Schule, B.; Guerra-Crespo, M. Alpha-Synuclein Physiology and Pathology: A Perspective on Cellular Structures and Organelles. Front. Neurosci. 2019, 13, 1399. [Google Scholar] [CrossRef] [PubMed]
  24. Lazarevic, V.; Yang, Y.; Paslawski, W.; Svenningsson, P. alpha-Synuclein induced cholesterol lowering increases tonic and reduces depolarization-evoked synaptic vesicle recycling and glutamate release. NPJ Parkinsons Dis. 2022, 8, 71. [Google Scholar] [CrossRef] [PubMed]
  25. Kachappilly, N.; Srivastava, J.; Swain, B.P.; Thakur, P. Interaction of alpha-synuclein with lipids. Methods Cell Biol. 2022, 169, 43–66. [Google Scholar] [CrossRef]
  26. Uceda, A.B.; Frau, J.; Vilanova, B.; Adrover, M. Glycation of alpha-synuclein hampers its binding to synaptic-like vesicles and its driving effect on their fusion. Cell Mol. Life Sci. 2022, 79, 342. [Google Scholar] [CrossRef]
  27. Sulzer, D.; Edwards, R.H. The physiological role of alpha-synuclein and its relationship to Parkinson’s Disease. J. Neurochem. 2019, 150, 475–486. [Google Scholar] [CrossRef]
  28. Burre, J.; Sharma, M.; Tsetsenis, T.; Buchman, V.; Etherton, M.R.; Sudhof, T.C. Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 2010, 329, 1663–1667. [Google Scholar] [CrossRef]
  29. Guo, J.T.; Chen, A.Q.; Kong, Q.; Zhu, H.; Ma, C.M.; Qin, C. Inhibition of vesicular monoamine transporter-2 activity in alpha-synuclein stably transfected SH-SY5Y cells. Cell Mol. Neurobiol. 2008, 28, 35–47. [Google Scholar] [CrossRef]
  30. Carnazza, K.E.; Komer, L.E.; Xie, Y.X.; Pineda, A.; Briano, J.A.; Gao, V.; Na, Y.; Ramlall, T.; Buchman, V.L.; Eliezer, D.; et al. Synaptic vesicle binding of alpha-synuclein is modulated by beta- and gamma-synucleins. Cell Rep. 2022, 39, 110675. [Google Scholar] [CrossRef]
  31. Carnazza, K.E.; Komer, L.E.; Pineda, A.; Na, Y.; Ramlall, T.; Buchman, V.L.; Eliezer, D.; Sharma, M.; Burre, J. Beta- and gamma-synucleins modulate synaptic vesicle-binding of alpha-synuclein. bioRxiv 2020. [Google Scholar] [CrossRef]
  32. Scheibe, C.; Karreman, C.; Schildknecht, S.; Leist, M.; Hauser, K. Synuclein Family Members Prevent Membrane Damage by Counteracting alpha-Synuclein Aggregation. Biomolecules 2021, 11, 1067. [Google Scholar] [CrossRef] [PubMed]
  33. Yates, D. Processing alpha-synuclein interactions. Nat. Rev. Neurosci. 2022, 23, 456–457. [Google Scholar] [CrossRef] [PubMed]
  34. Liu, C.; Zhao, Y.; Xi, H.; Jiang, J.; Yu, Y.; Dong, W. The Membrane Interaction of Alpha-Synuclein. Front. Cell Neurosci. 2021, 15, 633727. [Google Scholar] [CrossRef] [PubMed]
  35. Jeannotte, A.M.; McCarthy, J.G.; Sidhu, A. Desipramine induced changes in the norepinephrine transporter, alpha- and gamma-synuclein in the hippocampus, amygdala and striatum. Neurosci. Lett. 2009, 467, 86–89. [Google Scholar] [CrossRef]
  36. Bu, M.; Farrer, M.J.; Khoshbouei, H. Dynamic control of the dopamine transporter in neurotransmission and homeostasis. NPJ Parkinsons Dis. 2021, 7, 22. [Google Scholar] [CrossRef]
  37. Threlfell, S.; Mohammadi, A.S.; Ryan, B.J.; Connor-Robson, N.; Platt, N.J.; Anand, R.; Serres, F.; Sharp, T.; Bengoa-Vergniory, N.; Wade-Martins, R.; et al. Striatal Dopamine Transporter Function Is Facilitated by Converging Biology of alpha-Synuclein and Cholesterol. Front. Cell Neurosci. 2021, 15, 658244. [Google Scholar] [CrossRef]
  38. Longhena, F.; Faustini, G.; Missale, C.; Pizzi, M.; Bellucci, A. Dopamine Transporter/alpha-Synuclein Complexes Are Altered in the Post Mortem Caudate Putamen of Parkinson’s Disease: An In Situ Proximity Ligation Assay Study. Int. J. Mol. Sci. 2018, 19, 1611. [Google Scholar] [CrossRef]
  39. Lotharius, J.; Barg, S.; Wiekop, P.; Lundberg, C.; Raymon, H.K.; Brundin, P. Effect of mutant alpha-synuclein on dopamine homeostasis in a new human mesencephalic cell line. J. Biol. Chem. 2002, 277, 38884–38894. [Google Scholar] [CrossRef]
  40. Ghamgosha, M.; Latifi, A.M.; Meftahi, G.H.; Mohammadi, A. Cellular, Molecular and Non-Pharm.ogical Therapeutic Advances for the Treatment of Parkinson’s Disease: Separating Hope from Hype. Curr. Gene. Ther. 2018, 18, 206–224. [Google Scholar] [CrossRef]
  41. Wersinger, C.; Sidhu, A. Attenuation of dopamine transporter activity by alpha-synuclein. Neurosci. Lett. 2003, 340, 189–192. [Google Scholar] [CrossRef]
  42. Bridi, J.C.; Hirth, F. Mechanisms of alpha-Synuclein Induced Synaptopathy in Parkinson’s Disease. Front. Neurosci. 2018, 12, 80. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Yavich, L.; Tanila, H.; Vepsalainen, S.; Jakala, P. Role of alpha-synuclein in presynaptic dopamine recruitment. J. Neurosci. 2004, 24, 11165–11170. [Google Scholar] [CrossRef] [PubMed]
  44. Surguchov, A. Molecular and cellular biology of synucleins. Int. Rev. Cell Mol. Biol. 2008, 270, 225–317. [Google Scholar] [CrossRef]
  45. Fanning, S.; Selkoe, D.; Dettmer, U. Parkinson’s disease: Proteinopathy or lipidopathy? NPJ Parkinsons Dis 2020, 6, 3. [Google Scholar] [CrossRef]
  46. Millership, S.; Ninkina, N.; Rochford, J.J.; Buchman, V.L. gamma-synuclein is a novel player in the control of body lipid metabolism. Adipocyte 2013, 2, 276–280. [Google Scholar] [CrossRef]
  47. da Costa, C.A.; Masliah, E.; Checler, F. Beta-synuclein displays an antiapoptotic p53-dependent phenotype and protects neurons from 6-hydroxydopamine-induced caspase 3 activation: Cross-talk with alpha-synuclein and implication for Parkinson’s disease. J. Biol. Chem. 2003, 278, 37330–37335. [Google Scholar] [CrossRef]
  48. Brockhaus, K.; Bohm, M.R.R.; Melkonyan, H.; Thanos, S. Age-related Beta-synuclein Alters the p53/Mdm2 Pathway and Induces the Apoptosis of Brain Microvascular Endothelial Cells In Vitro. Cell Transpl. 2018, 27, 796–813. [Google Scholar] [CrossRef]
  49. Martinez, J.H.; Fuentes, F.; Vanasco, V.; Alvarez, S.; Alaimo, A.; Cassina, A.; Coluccio Leskow, F.; Velazquez, F. Alpha-synuclein mitochondrial interaction leads to irreversible translocation and complex I impairment. Arch. Biochem. Biophys. 2018, 651, 1–12. [Google Scholar] [CrossRef]
  50. Wang, X.; Becker, K.; Levine, N.; Zhang, M.; Lieberman, A.P.; Moore, D.J.; Ma, J. Pathogenic alpha-synuclein aggregates preferentially bind to mitochondria and affect cellular respiration. Acta Neuropathol. Commun. 2019, 7, 41. [Google Scholar] [CrossRef]
  51. Rostovtseva, T.K.; Gurnev, P.A.; Protchenko, O.; Hoogerheide, D.P.; Yap, T.L.; Philpott, C.C.; Lee, J.C.; Bezrukov, S.M. alpha-Synuclein Shows High Affinity Interaction with Voltage-dependent Anion Channel, Suggesting Mechanisms of Mitochondrial Regulation and Toxicity in Parkinson Disease. J. Biol. Chem. 2015, 290, 18467–18477. [Google Scholar] [CrossRef]
  52. Hoogerheide, D.P.; Rostovtseva, T.K.; Bezrukov, S.M. Exploring lipid-dependent conformations of membrane-bound alpha-synuclein with the VDAC nanopore. Biochim. Biophys. Acta Biomembr. 2021, 1863, 183643. [Google Scholar] [CrossRef] [PubMed]
  53. McHugh, P.C.; Wright, J.A.; Brown, D.R. Transcriptional regulation of the beta-synuclein 5′-promoter metal response element by metal transcription factor-1. PLoS ONE 2011, 6, e17354. [Google Scholar] [CrossRef] [PubMed]
  54. Rodriguez, E.E.; Rios, A.; Trujano-Ortiz, L.G.; Villegas, A.; Castaneda-Hernandez, G.; Fernandez, C.O.; Gonzalez, F.J.; Quintanar, L. Comparing the copper binding features of alpha and beta synucleins. J. Inorg. Biochem. 2022, 229, 111715. [Google Scholar] [CrossRef] [PubMed]
  55. Finkbeiner, S. The Autophagy Lysosomal Pathway and Neurodegeneration. Cold Spring Harb. Perspect Biol. 2020, 12, a033993. [Google Scholar] [CrossRef] [PubMed]
  56. Popova, B.; Kleinknecht, A.; Arendarski, P.; Mischke, J.; Wang, D.; Braus, G.H. Sumoylation Protects Against beta-Synuclein Toxicity in Yeast. Front. Mol. Neurosci. 2018, 11, 94. [Google Scholar] [CrossRef]
  57. Ye, Q.; Peng, Y.; Huang, F.; Chen, J.; Xu, Y.; Li, Y.; Liu, S.; Huang, L. gamma-Synuclein is Closely Involved in Autophagy that Protects Colon Cancer Cell from Endoplasmic Reticulum Stress. Anticancer Agents Med. Chem. 2021, 21, 2385–2396. [Google Scholar] [CrossRef]
  58. Madsen, D.A.; Schmidt, S.I.; Blaabjerg, M.; Meyer, M. Interaction between Parkin and alpha-Synuclein in PARK2-Mediated Parkinson’s Disease. Cells 2021, 10, 283. [Google Scholar] [CrossRef]
  59. Tanaka, Y.; Engelender, S.; Igarashi, S.; Rao, R.K.; Wanner, T.; Tanzi, R.E.; Sawa, A.; Dawson, V.L.; Dawson, T.M.; Ross, C.A. Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. Hum. Mol. Genet. 2001, 10, 919–926. [Google Scholar] [CrossRef]
  60. Barba, L.; Paolini Paoletti, F.; Bellomo, G.; Gaetani, L.; Halbgebauer, S.; Oeckl, P.; Otto, M.; Parnetti, L. Alpha and Beta Synucleins: From Pathophysiology to Clinical Application as Biomarkers. Mov. Disord. 2022, 37, 669–683. [Google Scholar] [CrossRef]
  61. Hanson, K.A.; Kim, S.H.; Wassarman, D.A.; Tibbetts, R.S. Ubiquilin modifies TDP-43 toxicity in a Drosophila model of amyotrophic lateral sclerosis (ALS). J. Biol. Chem. 2010, 285, 11068–11072. [Google Scholar] [CrossRef]
  62. Zhou, R.M.; Huang, Y.X.; Li, X.L.; Chen, C.; Shi, Q.; Wang, G.R.; Tian, C.; Wang, Z.Y.; Jing, Y.Y.; Gao, C.; et al. Molecular interaction of alpha-synuclein with tubulin influences on the polymerization of microtubule in vitro and structure of microtubule in cells. Mol. Biol. Rep. 2010, 37, 3183–3192. [Google Scholar] [CrossRef] [PubMed]
  63. Liu, Y.; Tapia, M.L.; Yeh, J.; He, R.C.; Pomerleu, D.; Lee, R.K. Differential Gamma-Synuclein Expression in Acute and Chronic Retinal Ganglion Cell Death in the Retina and Optic Nerve. Mol. Neurobiol. 2020, 57, 698–709. [Google Scholar] [CrossRef] [PubMed]
  64. Tarasova, T.V.; Lytkina, O.A.; Goloborshcheva, V.V.; Skuratovskaya, L.N.; Antohin, A.I.; Ovchinnikov, R.K.; Kukharsky, M.S. Genetic inactivation of alpha-synuclein affects embryonic development of dopaminergic neurons of the substantia nigra, but not the ventral tegmental area, in mouse brain. PeerJ 2018, 6, e4779. [Google Scholar] [CrossRef] [PubMed]
  65. Norris, E.H.; Giasson, B.I.; Lee, V.M. Alpha-synuclein: Normal function and role in neurodegenerative diseases. Curr. Top. Dev. Biol. 2004, 60, 17–54. [Google Scholar] [CrossRef]
  66. Quilty, M.C.; Gai, W.P.; Pountney, D.L.; West, A.K.; Vickers, J.C. Localization of alpha-, beta-, and gamma-synuclein during neuronal development and alterations associated with the neuronal response to axonal trauma. Exp. Neurol. 2003, 182, 195–207. [Google Scholar] [CrossRef]
  67. Beitz, J.M. Parkinson’s disease: A review. Front. Biosci. 2014, 6, 65–74. [Google Scholar] [CrossRef]
  68. Hayes, M.T. Parkinson’s Disease and Parkinsonism. Am. J. Med. 2019, 132, 802–807. [Google Scholar] [CrossRef]
  69. Tysnes, O.B.; Storstein, A. Epidemiology of Parkinson’s disease. J. Neural. Transm. 2017, 124, 901–905. [Google Scholar] [CrossRef]
  70. Cardoso, F.; Jankovic, J. Movement disorders. Neurol. Clin. 1993, 11, 625–638. [Google Scholar] [CrossRef]
  71. Keener, A.M.; Bordelon, Y.M. Parkinsonism. Semin. Neurol. 2016, 36, 330–334. [Google Scholar] [CrossRef]
  72. Kalia, L.V.; Lang, A.E. Parkinson disease in 2015: Evolving basic, pathological and clinical concepts in PD. Nat. Rev. Neurol. 2016, 12, 65–66. [Google Scholar] [CrossRef] [PubMed]
  73. Reich, S.G.; Savitt, J.M. Parkinson’s Disease. Med. Clin. N. Am. 2019, 103, 337–350. [Google Scholar] [CrossRef] [PubMed]
  74. Riederer, P.; Berg, D.; Casadei, N.; Cheng, F.; Classen, J.; Dresel, C.; Jost, W.; Kruger, R.; Muller, T.; Reichmann, H.; et al. alpha-Synuclein in Parkinson’s disease: Causal or bystander? J. Neural. Transm. 2019, 126, 815–840. [Google Scholar] [CrossRef]
  75. Polymeropoulos, M.H.; Lavedan, C.; Leroy, E.; Ide, S.E.; Dehejia, A.; Dutra, A.; Pike, B.; Root, H.; Rubenstein, J.; Boyer, R.; et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 1997, 276, 2045–2047. [Google Scholar] [CrossRef] [PubMed]
  76. Spillantini, M.G.; Schmidt, M.L.; Lee, V.M.; Trojanowski, J.Q.; Jakes, R.; Goedert, M. Alpha-synuclein in Lewy bodies. Nature 1997, 388, 839–840. [Google Scholar] [CrossRef]
  77. Goedert, M.; Jakes, R.; Spillantini, M.G. The Synucleinopathies: Twenty Years On. J. Parkinsons Dis. 2017, 7, S51–S69. [Google Scholar] [CrossRef]
  78. Gadhe, L.; Sakunthala, A.; Mukherjee, S.; Gahlot, N.; Bera, R.; Sawner, A.S.; Kadu, P.; Maji, S.K. Intermediates of alpha-synuclein aggregation: Implications in Parkinson’s disease pathogenesis. Biophys. Chem. 2022, 281, 106736. [Google Scholar] [CrossRef]
  79. Sharon, R.; Bar-Joseph, I.; Frosch, M.P.; Walsh, D.M.; Hamilton, J.A.; Selkoe, D.J. The formation of highly soluble oligomers of alpha-synuclein is regulated by fatty acids and enhanced in Parkinson’s disease. Neuron 2003, 37, 583–595. [Google Scholar] [CrossRef]
  80. Paleologou, K.E.; Kragh, C.L.; Mann, D.M.; Salem, S.A.; Al-Shami, R.; Allsop, D.; Hassan, A.H.; Jensen, P.H.; El-Agnaf, O.M. Detection of elevated levels of soluble alpha-synuclein oligomers in post-mortem brain extracts from patients with dementia with Lewy bodies. Brain 2009, 132, 1093–1101. [Google Scholar] [CrossRef]
  81. Park, M.J.; Cheon, S.M.; Bae, H.R.; Kim, S.H.; Kim, J.W. Elevated levels of alpha-synuclein oligomer in the cerebrospinal fluid of drug-naive patients with Parkinson’s disease. J. Clin. Neurol. 2011, 7, 215–222. [Google Scholar] [CrossRef]
  82. El-Agnaf, O.M.; Salem, S.A.; Paleologou, K.E.; Curran, M.D.; Gibson, M.J.; Court, J.A.; Schlossmacher, M.G.; Allsop, D. Detection of oligomeric forms of alpha-synuclein protein in human plasma as a potential biomarker for Parkinson’s disease. FASEB J 2006, 20, 419–425. [Google Scholar] [CrossRef] [PubMed]
  83. Gruden, M.A.; Davidova, T.V.; Yanamandra, K.; Kucheryanu, V.G.; Morozova-Roche, L.A.; Sherstnev, V.V.; Sewell, R.D. Nasal inoculation with alpha-synuclein aggregates evokes rigidity, locomotor deficits and immunity to such misfolded species as well as dopamine. Behav. Brain Res. 2013, 243, 205–212. [Google Scholar] [CrossRef] [PubMed]
  84. Pajares, M.; Rojo, A.I.; Manda, G.; Bosca, L.; Cuadrado, A. Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications. Cells 2020, 9, 1687. [Google Scholar] [CrossRef] [PubMed]
  85. Langston, J.W. The MPTP Story. J. Parkinsons Dis. 2017, 7, S11–S19. [Google Scholar] [CrossRef]
  86. Vivacqua, G.; Biagioni, F.; Busceti, C.L.; Ferrucci, M.; Madonna, M.; Ryskalin, L.; Yu, S.; D’Este, L.; Fornai, F. Motor Neurons Pathology After Chronic Exposure to MPTP in Mice. Neurotox. Res. 2020, 37, 298–313. [Google Scholar] [CrossRef]
  87. Fox, S.H.; Brotchie, J.M. The MPTP-lesioned non-human primate models of Parkinson’s disease. Past, present, and future. Prog. Brain Res. 2010, 184, 133–157. [Google Scholar] [CrossRef]
  88. Johannessen, J.N.; Sobotka, T.J.; Weise, V.K.; Markey, S.P. Prolonged alterations in canine striatal dopamine metabolism following subtoxic doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 4′-amino-MPTP are linked to the persistence of pyridinium metabolites. J. Neurochem. 1991, 57, 981–990. [Google Scholar] [CrossRef]
  89. Aznavour, N.; Cendres-Bozzi, C.; Lemoine, L.; Buda, C.; Sastre, J.P.; Mincheva, Z.; Zimmer, L.; Lin, J.S. MPTP animal model of Parkinsonism: Dopamine cell death or only tyrosine hydroxylase impairment? A study using PET imaging, autoradiography, and immunohistochemistry in the cat. CNS Neurosci. Ther. 2012, 18, 934–941. [Google Scholar] [CrossRef]
  90. Sokolowski, A.L.; Larsson, B.S.; Lindquist, N.G. Distribution of 1-(3H)-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (3H-MPTP) in the frog: Uptake in neuromelanin. Pharm. Toxicol. 1990, 66, 252–258. [Google Scholar] [CrossRef]
  91. Ya, V.M. Experimental reproduction of catecholamine deficiency states and the problem of parkinsonism. Neurophysiology 1990, 22, 401–414. (In Russian) [Google Scholar]
  92. Sablin, S.O.; Krueger, M.J.; Bachurin, S.O.; Solyakov, L.S.; Efange, S.M.; Singer, T.P. Oxidation products arising from the action of monoamine oxidase B on 1-methyl-4-benzyl-1,2,3,6-tetrahydropyridine, a nonneurotoxic analogue of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J. Neurochem. 1994, 62, 2012–2016. [Google Scholar] [CrossRef] [PubMed]
  93. Mayer, R.A.; Kindt, M.V.; Heikkila, R.E. Prevention of the nigrostriatal toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by inhibitors of 3,4-dihydroxyphenylethylamine transport. J. Neurochem. 1986, 47, 1073–1079. [Google Scholar] [CrossRef] [PubMed]
  94. Mat Taib, C.N.; Mustapha, M. MPTP-induced mouse model of Parkinson’s disease: A promising direction of therapeutic strategies. Bosn. J. Basic Med. Sci. 2020, 21, 422–433. [Google Scholar] [CrossRef] [PubMed]
  95. Wu, W.J.; Lu, C.W.; Wang, S.E.; Lin, C.L.; Su, L.Y.; Wu, C.H. MPTP toxicity causes vocal, auditory, orientation and movement defects in the echolocation bat. Neuroreport 2021, 32, 125–134. [Google Scholar] [CrossRef]
  96. Haga, H.; Matsuo, K.; Yabuki, Y.; Zhang, C.; Han, F.; Fukunaga, K. Enhancement of ATP production ameliorates motor and cognitive impairments in a mouse model of MPTP-induced Parkinson’s disease. Neurochem. Int. 2019, 129, 104492. [Google Scholar] [CrossRef]
  97. Vyas, I.; Heikkila, R.E.; Nicklas, W.J. Studies on the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: Inhibition of NAD-linked substrate oxidation by its metabolite, 1-methyl-4-phenylpyridinium. J. Neurochem. 1986, 46, 1501–1507. [Google Scholar] [CrossRef]
  98. Prasad, E.M.; Hung, S.Y. Behavioral Tests in Neurotoxin-Induced Animal Models of Parkinson’s Disease. Antioxidants 2020, 9, 1007. [Google Scholar] [CrossRef]
  99. Rossetti, Z.L.; Sotgiu, A.; Sharp, D.E.; Hadjiconstantinou, M.; Neff, N.H. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and free radicals in vitro. Biochem. Pharm. 1988, 37, 4573–4574. [Google Scholar] [CrossRef]
  100. Przedborski, S.; Chen, Q.; Vila, M.; Giasson, B.I.; Djaldatti, R.; Vukosavic, S.; Souza, J.M.; Jackson-Lewis, V.; Lee, V.M.; Ischiropoulos, H. Oxidative post-translational modifications of alpha-synuclein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease. J. Neurochem. 2001, 76, 637–640. [Google Scholar] [CrossRef]
  101. Baranyi, M.; Porceddu, P.F.; Goloncser, F.; Kulcsar, S.; Otrokocsi, L.; Kittel, A.; Pinna, A.; Frau, L.; Huleatt, P.B.; Khoo, M.L.; et al. Novel (Hetero)arylalkenyl propargylamine compounds are protective in toxin-induced models of Parkinson’s disease. Mol. Neurodegener 2016, 11, 6. [Google Scholar] [CrossRef]
  102. Wada, M.; Ang, M.J.; Weerasinghe-Mudiyanselage, P.D.E.; Kim, S.H.; Kim, J.C.; Shin, T.; Moon, C. Behavioral characterization in MPTP/p mouse model of Parkinson’s disease. J. Integr. Neurosci. 2021, 20, 307–320. [Google Scholar] [CrossRef] [PubMed]
  103. Goloborshcheva, V.; Voronina, N.; Ovchinnikov, R.; Kucheryanu, V.; Morozov, S. MPTP-induced Parkinsonism in genetically modified mice. Pathogenesis 2021, 19, 12–23. (In Russian) [Google Scholar] [CrossRef]
  104. Speranza, L.; di Porzio, U.; Viggiano, D.; de Donato, A.; Volpicelli, F. Dopamine: The Neuromodulator of Long-Term Synaptic Plasticity, Reward and Movement Control. Cells 2021, 10, 735. [Google Scholar] [CrossRef] [PubMed]
  105. Goloborshcheva, V.V.N.; Ovchinnikov, R.; Kucheryanu, V.; Morozov, S. Morphometric analysis of dopaminergic neurons (substantia nigra) in the brain of MPTP treated alpha synuclein knockout mice. Pathogenesis 2021, 19, 32–37. (In Russian) [Google Scholar]
  106. Klivenyi, P.; Siwek, D.; Gardian, G.; Yang, L.; Starkov, A.; Cleren, C.; Ferrante, R.J.; Kowall, N.W.; Abeliovich, A.; Beal, M.F. Mice lacking alpha-synuclein are resistant to mitochondrial toxins. Neurobiol. Dis. 2006, 21, 541–548. [Google Scholar] [CrossRef]
  107. Zharikov, A.; Bai, Q.; De Miranda, B.R.; Van Laar, A.; Greenamyre, J.T.; Burton, E.A. Long-term RNAi knockdown of alpha-synuclein in the adult rat substantia nigra without neurodegeneration. Neurobiol. Dis. 2019, 125, 146–153. [Google Scholar] [CrossRef]
  108. Goloborshcheva, V.V.; Chaprov, K.D.; Teterina, E.V.; Ovchinnikov, R.; Buchman, V.L. Reduced complement of dopaminergic neurons in the substantia nigra pars compacta of mice with a constitutive “low footprint” genetic knockout of alpha-synuclein. Mol. Brain 2020, 13, 75. [Google Scholar] [CrossRef]
  109. Lehmensiek, V.; Tan, E.M.; Schwarz, J.; Storch, A. Expression of mutant alpha-synucleins enhances dopamine transporter-mediated MPP+ toxicity in vitro. Neuroreport 2002, 13, 1279–1283. [Google Scholar] [CrossRef]
  110. Van Laar, V.S.; Chen, J.; Zharikov, A.D.; Bai, Q.; Di Maio, R.; Dukes, A.A.; Hastings, T.G.; Watkins, S.C.; Greenamyre, J.T.; St Croix, C.M.; et al. alpha-Synuclein amplifies cytoplasmic peroxide flux and oxidative stress provoked by mitochondrial inhibitors in CNS dopaminergic neurons in vivo. Redox. Biol. 2020, 37, 101695. [Google Scholar] [CrossRef]
  111. Cabin, D.E.; Shimazu, K.; Murphy, D.; Cole, N.B.; Gottschalk, W.; McIlwain, K.L.; Orrison, B.; Chen, A.; Ellis, C.E.; Paylor, R.; et al. Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J. Neurosci. 2002, 22, 8797–8807. [Google Scholar] [CrossRef]
  112. Ninkina, N.; Tarasova, T.V.; Chaprov, K.D.; Roman, A.Y.; Kukharsky, M.S.; Kolik, L.G.; Ovchinnikov, R.; Ustyugov, A.A.; Durnev, A.D.; Buchman, V.L. Alterations in the nigrostriatal system following conditional inactivation of alpha-synuclein in neurons of adult and aging mice. Neurobiol. Aging. 2020, 91, 76–87. [Google Scholar] [CrossRef] [PubMed]
  113. Ninkina, N.N.; Tarasova, T.V.; Chaprov, K.D.; Goloborshcheva, V.V.; Bachurin, S.O.; Buchman, V.L. Synuclein Deficiency Decreases the Efficiency of Dopamine Uptake by Synaptic Vesicles. Dokl. Biochem. Biophys. 2019, 486, 168–170. [Google Scholar] [CrossRef] [PubMed]
  114. Connor-Robson, N.; Peters, O.M.; Millership, S.; Ninkina, N.; Buchman, V.L. Combinational losses of synucleins reveal their differential requirements for compensating age-dependent alterations in motor behavior and dopamine metabolism. Neurobiol. Aging. 2016, 46, 107–112. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Al-Wandi, A.; Ninkina, N.; Millership, S.; Williamson, S.J.; Jones, P.A.; Buchman, V.L. Absence of alpha-synuclein affects dopamine metabolism and synaptic markers in the striatum of aging mice. Neurobiol. Aging. 2010, 31, 796–804. [Google Scholar] [CrossRef]
  116. Pavia-Collado, R.; Rodriguez-Aller, R.; Alarcon-Aris, D.; Miquel-Rio, L.; Ruiz-Bronchal, E.; Paz, V.; Campa, L.; Galofre, M.; Sgambato, V.; Bortolozzi, A. Up and Down gamma-Synuclein Transcription in Dopamine Neurons Translates into Changes in Dopamine Neurotransmission and Behavioral Performance in Mice. Int. J. Mol. Sci. 2022, 23, 1807. [Google Scholar] [CrossRef]
  117. Thomas, B.; Mandir, A.S.; West, N.; Liu, Y.; Andrabi, S.A.; Stirling, W.; Dawson, V.L.; Dawson, T.M.; Lee, M.K. Resistance to MPTP-neurotoxicity in alpha-synuclein knockout mice is complemented by human alpha-synuclein and associated with increased beta-synuclein and Akt activation. PLoS ONE 2011, 6, e16706. [Google Scholar] [CrossRef]
  118. Hashimoto, M.; Bar-On, P.; Ho, G.; Takenouchi, T.; Rockenstein, E.; Crews, L.; Masliah, E. Beta-synuclein regulates Akt activity in neuronal cells. A possible mechanism for neuroprotection in Parkinson’s disease. J. Biol. Chem. 2004, 279, 23622–23629. [Google Scholar] [CrossRef]
  119. Miyazaki, I.; Asanuma, M. Neuron-Astrocyte Interactions in Parkinson’s Disease. Cells 2020, 9, 2623. [Google Scholar] [CrossRef]
  120. Gibrat, C.; Saint-Pierre, M.; Bousquet, M.; Levesque, D.; Rouillard, C.; Cicchetti, F. Differences between subacute and chronic MPTP mice models: Investigation of dopaminergic neuronal degeneration and alpha-synuclein inclusions. J. Neurochem. 2009, 109, 1469–1482. [Google Scholar] [CrossRef]
  121. Fornai, F.; Schluter, O.M.; Lenzi, P.; Gesi, M.; Ruffoli, R.; Ferrucci, M.; Lazzeri, G.; Busceti, C.L.; Pontarelli, F.; Battaglia, G.; et al. Parkinson-like syndrome induced by continuous MPTP infusion: Convergent roles of the ubiquitin-proteasome system and alpha-synuclein. Proc. Natl. Acad. Sci. USA 2005, 102, 3413–3418. [Google Scholar] [CrossRef]
  122. Gu, X.L.; Long, C.X.; Sun, L.; Xie, C.; Lin, X.; Cai, H. Astrocytic expression of Parkinson’s disease-related A53T alpha-synuclein causes neurodegeneration in mice. Mol. Brain 2010, 3, 12. [Google Scholar] [CrossRef] [PubMed]
  123. Sarafian, T.A.; Littlejohn, K.; Yuan, S.; Fernandez, C.; Cilluffo, M.; Koo, B.K.; Whitelegge, J.P.; Watson, J.B. Stimulation of synaptoneurosome glutamate release by monomeric and fibrillated alpha-synuclein. J. Neurosci. Res. 2017, 95, 1871–1887. [Google Scholar] [CrossRef] [PubMed]
  124. Yang, J.; Hertz, E.; Zhang, X.; Leinartaite, L.; Lundius, E.G.; Li, J.; Svenningsson, P. Overexpression of alpha-synuclein simultaneously increases glutamate NMDA receptor phosphorylation and reduces glucocerebrosidase activity. Neurosci. Lett. 2016, 611, 51–58. [Google Scholar] [CrossRef] [PubMed]
  125. Voronina, N.A.; Lisina, O.Y.; Krasilnikova, I.A.; Kucheryanu, V.G.; Kapitsa, I.G.; Voronina, T.A.; Surin, A.M. Influence of hemantane on changes in Ca 2+ and Na+ caused by activation of NMDA channels in cultured rat brain neurons. Neurochem. J. 2021, 15, 8–17. [Google Scholar] [CrossRef]
  126. Bashkatova, V. Metabotropic glutamate receptors and nitric oxide in dopaminergic neurotoxicity. World J. Psychiatry 2021, 11, 830–840. [Google Scholar] [CrossRef]
  127. Fairless, R.; Bading, H.; Diem, R. Pathophysiological Ionotropic Glutamate Signalling in Neuroinflammatory Disease as a Therapeutic Target. Front. Neurosci. 2021, 15, 741280. [Google Scholar] [CrossRef]
  128. Huls, S.; Hogen, T.; Vassallo, N.; Danzer, K.M.; Hengerer, B.; Giese, A.; Herms, J. AMPA-receptor-mediated excitatory synaptic transmission is enhanced by iron-induced alpha-synuclein oligomers. J. Neurochem. 2011, 117, 868–878. [Google Scholar] [CrossRef]
  129. Jensen, P.J.; Alter, B.J.; O’Malley, K.L. Alpha-synuclein protects naive but not dbcAMP-treated dopaminergic cell types from 1-methyl-4-phenylpyridinium toxicity. J. Neurochem. 2003, 86, 196–209. [Google Scholar] [CrossRef]
  130. Rosencrans, W.M.; Aguilella, V.M.; Rostovtseva, T.K.; Bezrukov, S.M. alpha-Synuclein emerges as a potent regulator of VDAC-facilitated calcium transport. Cell Calcium 2021, 95, 102355. [Google Scholar] [CrossRef]
Biomedicines 10 02278 g001 550
Figure 1. The role of synucleins in the mechanisms of SNpc DA neurons during MPTP-induced parkinsonism. Key regulatory factors include the regulatory activity of all synucleins toward the presynaptic membrane of the dopamine transporter (DAT); increased DAT/VMAT-2 ratio and SNARE assembly due to the presence of alpha-synuclein and support from other members of the synuclein family; the inability of beta-synuclein in the presence of alpha- and gamma-synucleins to potentiate VMAT-2-dependent MPP+ capture to further sequester these molecules; the involvement of alpha-synuclein in the neuroinflammatory response; and glutamate toxicity induced by glial cells. These, as well as other unexplored effects of alpha-synuclein binding and penetration into damaged mitochondria, may have a special effect on the MPTP-induced death of DA neurons. Created with BioRender.com (accessed on 2 November 2021).
Figure 1. The role of synucleins in the mechanisms of SNpc DA neurons during MPTP-induced parkinsonism. Key regulatory factors include the regulatory activity of all synucleins toward the presynaptic membrane of the dopamine transporter (DAT); increased DAT/VMAT-2 ratio and SNARE assembly due to the presence of alpha-synuclein and support from other members of the synuclein family; the inability of beta-synuclein in the presence of alpha- and gamma-synucleins to potentiate VMAT-2-dependent MPP+ capture to further sequester these molecules; the involvement of alpha-synuclein in the neuroinflammatory response; and glutamate toxicity induced by glial cells. These, as well as other unexplored effects of alpha-synuclein binding and penetration into damaged mitochondria, may have a special effect on the MPTP-induced death of DA neurons. Created with BioRender.com (accessed on 2 November 2021).
Biomedicines 10 02278 g001
Table
Table 1. Physiological functions of synuclein proteins.
Table 1. Physiological functions of synuclein proteins.
Functionsα-synβ-synγ-synRef.
Neurotransmission✔✔✔[22,23,24,25,26,27]
Chaperoning✔✔✔[32,33,34]
SNARE assembly✔MaintenanceMaintenance[28,29,30,31]
DAT transporter delivery to the presynapse✔✔✔[11,31,35]
Regulation of DAT transporter activity✔NAMaintenance[36,37,38]
Regulation of dopamine homeostasis✔?NA[27,39,40,41,42,43,44]
Potentiation of vesicular dopamine uptakeNA✔NA[4]
Lipid structure or morphology changes✔✔✔[11,31,45]
Regulation of lipid metabolismNANA✔[46]
Anti-apoptosis✔✔NA[47,48]
Mitochondrial regulation?NANA[49,50,51,52]
Regulation of cellular metal homeostasisNA✔NA[11,53,54]
Regulation of the autophagic–lysosomal pathwayNA?✔[55,56,57]
Interaction with proteasomes✔✔✔[58,59,60]
Cytoskeleton stabilization?NA✔[61,62,63]
Regulation of the growth of neurons in SNpc✔NANA[64]
Regeneration of damaged neurons???[65,66]
✔: involved; NA: not available; ?: hypothesis.
Table
Table 2. Main phenotypic changes in synuclein-knockout animals before and after MPTP injections.
Table 2. Main phenotypic changes in synuclein-knockout animals before and after MPTP injections.
EffectMPTP *α-syn KOβ-syn KOγ-syn KOαβγ-syn KO
Clinical manifestation–≈≈≈≈
+✔NANA✖
Striatal dopamine–≈▼≈▼
+▼▼NA▼
DAT expression–▼NANANA
+NANANANA
SNpc neurons–▼≈▼≈
+resistant ▼resistant ▼
≈: similar to wild-type animals; ✔: presence; ✖: absence; ▼: decrease; NA: not available; *: subchronic MPTP administration.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Goloborshcheva, V.V.; Kucheryanu, V.G.; Voronina, N.A.; Teterina, E.V.; Ustyugov, A.A.; Morozov, S.G. Synuclein Proteins in MPTP-Induced Death of Substantia Nigra Pars Compacta Dopaminergic Neurons. Biomedicines 2022, 10, 2278. https://doi.org/10.3390/biomedicines10092278

AMA Style

Goloborshcheva VV, Kucheryanu VG, Voronina NA, Teterina EV, Ustyugov AA, Morozov SG. Synuclein Proteins in MPTP-Induced Death of Substantia Nigra Pars Compacta Dopaminergic Neurons. Biomedicines. 2022; 10(9):2278. https://doi.org/10.3390/biomedicines10092278

Chicago/Turabian Style

Goloborshcheva, Valeria V., Valerian G. Kucheryanu, Natalia A. Voronina, Ekaterina V. Teterina, Aleksey A. Ustyugov, and Sergei G. Morozov. 2022. "Synuclein Proteins in MPTP-Induced Death of Substantia Nigra Pars Compacta Dopaminergic Neurons" Biomedicines 10, no. 9: 2278. https://doi.org/10.3390/biomedicines10092278

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop