Recent Advances in Understanding of the Role of Synuclein Family Members in Health and Disease Volume II

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 8739

Special Issue Editor


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Guest Editor
School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK
Interests: neorodegeneration; mechanisms of proteinopaty; synuclein family; physiological functions of synucleins; chemical neurotransmission; dopamine; synucleinsynuclein-associated pathology
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Special Issue Information

Dear Colleagues,

Extensive studies of α-synuclein function and dysfunction revealed its involvement in multiple normal and aberrant molecular processes and consequently, various effects on the nervous system cell biology. However, certain other types of cells normally express this protein, and they may also be affected by α-synuclein dysfunction and thus contribute to pathological changes in α-synucleinopathies. It would be beneficial to summarise scattered data on these aspects of α-synuclein biology and pathology. Recent studies draw attention to the other two members of the family, b-synuclein and g-synuclein, whose role in homeostasis and pathology is still poorly understood. Three members of the family share many structural properties and have an overlapping pattern of expression and intracellular distribution in the developing and adult nervous system, which point to functional redundancy within the family. However, each synuclein has its own functions unshared with two other synucleins and in some cellular mechanisms and pathways, these functions could be antagonistic rather than synergistic.

This Special Issue aims to highlight the most recent research on both already well-known and emerging aspects of synuclein family biology and the role of the dysfunction of these proteins in neurodegenerative and other pathological conditions.

Dr. Natalia N. Ninkina
Guest Editor

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Keywords

  • synuclein family
  • alpha-synuclein
  • beta-synuclein
  • gamma-synuclein
  • physiological functions of synucleins
  • synucleins and lipids
  • function of synucleins outside of the nervous system
  • synuclein-associated pathology

Published Papers (6 papers)

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Research

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17 pages, 9546 KiB  
Article
Disruption of Electroencephalogram Coherence between Cortex/Striatum and Midbrain Dopaminergic Regions in the Knock-Out Mice with Combined Loss of Alpha, Beta, and Gamma Synucleins
by Vasily Vorobyov, Alexander Deev, Kirill Chaprov and Natalia Ninkina
Biomedicines 2024, 12(4), 881; https://doi.org/10.3390/biomedicines12040881 - 16 Apr 2024
Viewed by 566
Abstract
The malfunctioning of the brain synucleins is associated with pathogenesis of Parkinson’s disease. Synucleins’ ability to modulate various pre-synaptic processes suggests their modifying effects on the electroencephalogram (EEG) recorded from different brain structures. Disturbances in interrelations between them are critical for the onset [...] Read more.
The malfunctioning of the brain synucleins is associated with pathogenesis of Parkinson’s disease. Synucleins’ ability to modulate various pre-synaptic processes suggests their modifying effects on the electroencephalogram (EEG) recorded from different brain structures. Disturbances in interrelations between them are critical for the onset and evolution of neurodegenerative diseases. Recently, we have shown that, in mice lacking several synucleins, differences between the frequency spectra of EEG from different brain structures are correlated with specificity of synucleins’ combinations. Given that EEG spectra are indirect characteristics of inter-structural relations, in this study, we analyzed a coherence of instantaneous values for EEGs recorded from different structures as a direct measure of “functional connectivity” between them. Methods: EEG data from seven groups of knock-out (KO) mice with combined deletions of alpha, beta, and gamma synucleins versus a group of wild-type (WT) mice were compared. EEG coherence was estimated between the cortex (MC), putamen (Pt), ventral tegmental area (VTA), and substantia nigra (SN) in all combinations. Results: EEG coherence suppression, predominantly in the beta frequency band, was observed in KO mice versus WT littermates. The suppression was minimal in MC-Pt and VTA-SN interrelations in all KO groups and in all inter-structural relations in mice lacking either all synucleins or only beta synuclein. In other combinations of deleted synucleins, significant EEG coherence suppression in KO mice was dominant in relations with VTA and SN. Conclusion: Deletions of the synucleins produced significant attenuation of intra-cerebral EEG coherence depending on the imbalance of different types of synucleins. Full article
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14 pages, 2281 KiB  
Article
Early Effects of Alpha-Synuclein Depletion by Pan-Neuronal Inactivation of Encoding Gene on Electroencephalogram Coherence between Different Brain Regions in Mice
by Vasily Vorobyov, Alexander Deev, Olga Morozova, Zoya Oganesyan, Anastasia M. Krayushkina, Tamara A. Ivanova and Kirill Chaprov
Biomedicines 2023, 11(12), 3282; https://doi.org/10.3390/biomedicines11123282 - 12 Dec 2023
Viewed by 1069
Abstract
Inactivation of the Snca gene in young mice by chronic injections of tamoxifen (TAM), a selective estrogen receptor modifier, has been shown to decrease the level of alpha-synuclein, a key peptide in the pathogenesis of Parkinson’s disease. In young mice, different time courses [...] Read more.
Inactivation of the Snca gene in young mice by chronic injections of tamoxifen (TAM), a selective estrogen receptor modifier, has been shown to decrease the level of alpha-synuclein, a key peptide in the pathogenesis of Parkinson’s disease. In young mice, different time courses of the effect were observed in different brain areas, meaning associated disturbances in the intracerebral relations, namely in brain function after TAM-induced synucleinopathy. Methods: We analyzed electroencephalogram (EEG) coherence (“functional connectivity”) between the cortex (MC), putamen (Pt), and dopamine-producing brain regions (ventral tegmental area, VTA, and substantia nigra, SN) in two groups of two-month-old male mice. We compared EEG coherences in the conditional knockout Sncaflox/flox mice with those in their genetic background (C57Bl6J) one, two, and three months after chronic (for five days) intraperitoneal injections of TAM or the vehicle (corn oil). The EEG coherences in the TAM-treated group were compared with those in the alpha-synuclein knockout mice. Results: A significant suppression of EEG coherence in the TAM-treated mice versus the vehicle group was observed in all inter-structural relations, with the exception of MC-VTA at one and three months and VTA-SN at two months after the injections. Suppressive changes in EEG coherence were observed in the alpha-synuclein knockout mice as well; the changes were similar to those in TAM-treated mice three months after treatment. Conclusion: our data demonstrate a combined time-dependent suppressive effect induced by TAM on intracerebral EEG coherence. Full article
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14 pages, 2663 KiB  
Article
The Poly-Arginine Peptide R18D Interferes with the Internalisation of α-Synuclein Pre-Formed Fibrils in STC-1 Enteroendocrine Cells
by Anastazja M. Gorecki, Holly Spencer, Bruno P. Meloni and Ryan S. Anderton
Biomedicines 2023, 11(8), 2089; https://doi.org/10.3390/biomedicines11082089 - 25 Jul 2023
Viewed by 1657
Abstract
In Parkinson’s disease (PD), gut inflammation is hypothesised to contribute to α-synuclein aggregation, but gastrointestinal α-synuclein expression is poorly characterised. Cationic arginine-rich peptides (CARPs) are an emerging therapeutic option that exerts various neuroprotective effects and may target the transmission of protein aggregates. This [...] Read more.
In Parkinson’s disease (PD), gut inflammation is hypothesised to contribute to α-synuclein aggregation, but gastrointestinal α-synuclein expression is poorly characterised. Cationic arginine-rich peptides (CARPs) are an emerging therapeutic option that exerts various neuroprotective effects and may target the transmission of protein aggregates. This study aimed to investigate endogenous α-synuclein expression in enteroendocrine STC-1 cells and the potential of the CARP, R18D (18-mer of D-arginine), to prevent internalisation of pre-formed α-synuclein fibrils (PFFs) in enteroendocrine cells in vitro. Through confocal microscopy, the immunoreactivity of full-length α-synuclein and the serine-129 phosphorylated form (pS129) was investigated in STC-1 (mouse enteroendocrine) cells. Thereafter, STC-1 cells were exposed to PFFs tagged with Alexa-Fluor 488 (PFF-488) for 2 and 24 h and R18D-FITC for 10 min. After confirming the uptake of both PFFs and R18D-FITC through fluorescent microscopy, STC-1 cells were pre-treated with R18D (5 or 10 μM) for 10 min prior to 2 h of PFF-488 exposure. Immunoreactivity for endogenous α-synuclein and pS129 was evident in STC-1 cells, with prominent pS129 staining along cytoplasmic processes and in perinuclear areas. STC-1 cells internalised PFFs, confirmed through co-localisation of PFF-488 and human-specific α-synuclein immunoreactivity. R18D-FITC entered STC-1 cells within 10 min and pre-treatment of STC-1 cells with R18D interfered with PFF uptake. The endogenous presence of α-synuclein in enteroendocrine cells, coupled with their rapid uptake of PFFs, demonstrates a potential for pathogenic spread of α-synuclein aggregates in the gut. R18D is a novel therapeutic approach to reduce the intercellular transmission of α-synuclein pathology. Full article
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13 pages, 3088 KiB  
Article
Age-Related Modifications of Electroencephalogram Coherence in Mice Models of Alzheimer’s Disease and Amyotrophic Lateral Sclerosis
by Vasily Vorobyov, Alexander Deev, Kirill Chaprov, Aleksey A. Ustyugov and Ekaterina Lysikova
Biomedicines 2023, 11(4), 1151; https://doi.org/10.3390/biomedicines11041151 - 11 Apr 2023
Cited by 3 | Viewed by 1344
Abstract
Evident similarities in pathological features in aging and Alzheimer’s disease (AD) raise the question of a role for natural age-related adaptive mechanisms in the prevention/elimination of disturbances in interrelations between different brain areas. In our previous electroencephalogram (EEG) studies on 5xFAD- and FUS-transgenic [...] Read more.
Evident similarities in pathological features in aging and Alzheimer’s disease (AD) raise the question of a role for natural age-related adaptive mechanisms in the prevention/elimination of disturbances in interrelations between different brain areas. In our previous electroencephalogram (EEG) studies on 5xFAD- and FUS-transgenic mice, as models of AD and amyotrophic lateral sclerosis (ALS), this suggestion was indirectly confirmed. In the current study, age-related changes in direct EEG synchrony/coherence between the brain structures were evaluated. Methods: In 5xFAD mice of 6-, 9-, 12-, and 18-month ages and their wild-type (WT5xFAD) littermates, we analyzed baseline EEG coherence between the cortex, hippocampus/putamen, ventral tegmental area, and substantia nigra. Additionally, EEG coherence between the cortex and putamen was analyzed in 2- and 5-month-old FUS mice. Results: In the 5xFAD mice, suppressed levels of inter-structural coherence vs. those in WT5xFAD littermates were observed at ages of 6, 9, and 12 months. In 18-month-old 5xFAD mice, only the hippocampus ventral tegmental area coherence was significantly reduced. In 2-month-old FUS vs. WTFUS mice, the cortex–putamen coherence suppression, dominated in the right hemisphere, was observed. In 5-month-old mice, EEG coherence was maximal in both groups. Conclusion: Neurodegenerative pathologies are accompanied by the significant attenuation of intracerebral EEG coherence. Our data are supportive for the involvement of age-related adaptive mechanisms in intracerebral disturbances produced by neurodegeneration. Full article
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Review

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14 pages, 2215 KiB  
Review
On the Role of Iron in Idiopathic Parkinson’s Disease
by Sandro Huenchuguala and Juan Segura-Aguilar
Biomedicines 2023, 11(11), 3094; https://doi.org/10.3390/biomedicines11113094 - 20 Nov 2023
Cited by 4 | Viewed by 1467
Abstract
The transition metal characteristics of iron allow it to play a fundamental role in several essential aspects of human life such as the transport of oxygen through hemoglobin or the transport of electrons in the mitochondrial respiratory chain coupled to the synthesis of [...] Read more.
The transition metal characteristics of iron allow it to play a fundamental role in several essential aspects of human life such as the transport of oxygen through hemoglobin or the transport of electrons in the mitochondrial respiratory chain coupled to the synthesis of ATP. However, an excess or deficiency of iron is related to certain pathologies. The maintenance of iron homeostasis is essential to avoid certain pathologies related to iron excess or deficiency. The existence of iron deposits in postmortem tissues of Parkinson’s patients has been interpreted as evidence that iron plays a fundamental role in the degenerative process of the nigrostriatal system in this disease. The use of iron chelators has been successful in the treatment of diseases such as transfusion-dependent thalassemia and pantothenate kinase-associated neurodegeneration. However, a clinical study with the iron chelator deferiprone in patients with Parkinson’s disease has not shown positive effects but rather worsened clinical symptoms. This suggests that iron may not play a role in the degenerative process of Parkinson’s disease. Full article
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14 pages, 917 KiB  
Review
Controversial Properties of Amyloidogenic Proteins and Peptides: New Data in the COVID Era
by Andrei Surguchov, Fatemeh N. Emamzadeh, Mariya Titova and Alexei A. Surguchev
Biomedicines 2023, 11(4), 1215; https://doi.org/10.3390/biomedicines11041215 - 19 Apr 2023
Cited by 10 | Viewed by 2013
Abstract
For a long time, studies of amyloidogenic proteins and peptides (amyloidogenic PPs) have been focused basically on their harmful properties and association with diseases. A vast amount of research has investigated the structure of pathogenic amyloids forming fibrous deposits within or around cells [...] Read more.
For a long time, studies of amyloidogenic proteins and peptides (amyloidogenic PPs) have been focused basically on their harmful properties and association with diseases. A vast amount of research has investigated the structure of pathogenic amyloids forming fibrous deposits within or around cells and the mechanisms of their detrimental actions. Much less has been known about the physiologic functions and beneficial properties of amyloidogenic PPs. At the same time, amyloidogenic PPs have various useful properties. For example, they may render neurons resistant to viral infection and propagation and stimulate autophagy. We discuss here some of amyloidogenic PPs’ detrimental and beneficial properties using as examples beta-amyloid (β-amyloid), implicated in the pathogenesis of Alzheimer’s disease (AD), and α-synuclein—one of the hallmarks of Parkinson’s disease (PD). Recently amyloidogenic PPs’ antiviral and antimicrobial properties have attracted attention because of the COVID-19 pandemic and the growing threat of other viral and bacterial-induced diseases. Importantly, several COVID-19 viral proteins, e.g., spike, nucleocapsid, and envelope proteins, may become amyloidogenic after infection and combine their harmful action with the effect of endogenous APPs. A central area of current investigations is the study of the structural properties of amyloidogenic PPs, defining their beneficial and harmful properties, and identifying triggers that transform physiologically important amyloidogenic PPs into vicious substances. These directions are of paramount importance during the current SARS-CoV-2 global health crisis. Full article
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