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Recent Advances in α-Synuclein Neurobiology in Health and Disease

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: closed (15 March 2022) | Viewed by 17788

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Special Issue Editors

Dr. Maria Xilouri

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Guest Editor

Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece
Interests: alpha-synuclein; autophagy; Multiple System Atrophy (MSA); neurodegenerative diseases; oligodendrocytes; Parkinson’s disease (PD); propagation

Dr. Evangelia Emmanouilidou

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Guest Editor

Department of Chemistry, National and Kapodistrian University of Athens, 157 84 Zografou, Greece
Interests: neurodegenerative disorders; biochemistry

Dr. Alexia Polissidis

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Guest Editor

Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece
Interests: α-Synuclein; neurodegeneration; neuroinflammation; Parkinson

Special Issue Information

Dear Colleagues,

It has been almost 25 years since the discovery that Lewy body (LB) pathology, the key pathological hallmark of Parkinson disease (PD) and dementia with Lewy bodies (DLB), is immunoreactive for α-Synuclein (Spillantini et al. 1997). The same year, the first point mutation in the SNCA gene encoding for α-Synuclein, the alanine to threonine at position 53 (A53T) leading to autosomal dominant PD, was identified (Polymeropoulos et al, 1997). One year later, a strong α-Synuclein immunoreactivity in glial cytoplasmic inclusions (GCIs) of oligodendrocytes was found in human post-mortem brains of multiple system atrophy (MSA) (Wakabayashi et al, 1998). Ever since, substantial genetic, neuropathological and biochemical evidence implicates α-Synuclein in the pathogenesis of PD and related synucleinopathies. The presence of pathologically aggregated α-Synuclein along with components of the protein degradation machinery, such as ubiquitin and p62, in LBs and GCIs is considered to underlie the pathogenic cascade that eventually leads to the severe neurodegeneration and neuroinflammation that characterizes these diseases. Initial studies focused on the formation of intracellular aggregates composed of oligomeric or fibrillar forms of the protein as the principal causative link to neurodegeneration. Subsequent and more recent work uncovered various pathogenetic mechanisms, including, amongst others, dysregulation of mitochondrial activity and endoplasmic reticulum (ER)-Golgi trafficking, plasma membrane integrity, synaptic vesicle trafficking and function of the ubiquitin-proteasome (UPS) and the autophagy-lysosome pathway (ALP) (Vekrellis et al., 2011). In addition, α-Synuclein is proposed to undergo pathogenic misfolding and oligomerization into higher-order aggregated structures, revealing self-templating conformations, and to exert the ability of “prion-like” spreading between cells. The tendency of α-Synuclein to form aggregates lies in the core of its neurotoxic potential and strategies seeking to alleviate the total protein load (intracellular and extracellular) represent an obvious therapeutic approach. However, the development of effective therapeutic strategies to prevent degeneration in synucleinopathies is limited, due to the lack of knowledge regarding the precise mechanisms underlying the observed pathology.

This Special Issue aims to integrate the current knowledge regarding the physiological function of α-Synuclein and the mechanisms underlying its loss of function, in an attempt to pinpoint novel neuroprotective and ameliorative therapies to confront both the initiation and progression of disease processes.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but not limited to) the following:

α-Synuclein physiological function: Focus at the synapse
α-Synuclein strain heterogeneity and aggregation
Interrelationship of α-Synuclein with protein degradation pathways
In vitro and in vivo models of α-Synucleinopathy
α-Synuclein in the extracellular space
Therapeutic strategies targeting intracellular and extracellular α-Synuclein
α-Synuclein in the periphery

We look forward to receiving your contributions.

Dr. Maria Xilouri
Dr. Evangelia Emmanouilidou
Dr. Alexia Polissidis
Guest Editors

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

α-Synuclein
Synapse
Protein Aggregation
α-Synuclein Degradation
Propagation
Strains
Exosomes
Secretion

Published Papers (6 papers)

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Research

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14 pages, 2185 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Early Signs of Molecular Defects in iPSC-Derived Neural Stems Cells from Patients with Familial Parkinson’s Disease

by Elissavet Akrioti, Timokratis Karamitros, Panagiotis Gkaravelas, Georgia Kouroupi, Rebecca Matsas and Era Taoufik

Biomolecules 2022, 12(7), 876; https://doi.org/10.3390/biom12070876 - 23 Jun 2022

Cited by 4 | Viewed by 3462

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, classically associated with extensive loss of dopaminergic neurons of the substantia nigra pars compacta. The hallmark of the disease is the accumulation of pathogenic conformations of the presynaptic protein, α-synuclein (αSyn), and the formation of intraneuronal protein aggregate inclusions. Neurodegeneration of dopamine neurons leads to a prominent dopaminergic deficiency in the basal ganglia, responsible for motor disturbances. However, it is now recognized that the disease involves more widespread neuronal dysfunction, leading to early and late non-motor symptoms. The development of in vitro systems based on the differentiation of human-induced pluripotent stem cells provides us the unique opportunity to monitor alterations at the cellular and molecular level throughout the differentiation procedure and identify perturbations that occur early, even at the neuronal precursor stage. Here we aim to identify whether p.A53T-αSyn induced disturbances at the molecular level are already present in neural precursors. Towards this, we present data from transcriptomics analysis of control and p.A53T-αSyn NPCs showing altered expression in transcripts involved in axon guidance, adhesion, synaptogenesis, ion transport, and metabolism. The comparative analysis with the transcriptomics profile of p.A53T-αSyn neurons shows both distinct and overlapping pathways leading to neurodegeneration while meta-analysis with transcriptomics data from both neurodegenerative and neurodevelopmental disorders reveals that p.A53T-pathology has a significant overlap with the latter category. This is the first study showing that molecular dysregulation initiates early at the p.A53T-αSyn NPC level, suggesting that synucleinopathies may have a neurodevelopmental component. Full article

(This article belongs to the Special Issue Recent Advances in α-Synuclein Neurobiology in Health and Disease)

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12 pages, 4992 KiB

Open AccessArticle

Early Forms of α-Synuclein Pathology Are Associated with Neuronal Complex I Deficiency in the Substantia Nigra of Individuals with Parkinson’s Disease

by Irene Hana Flønes, Harald Nyland, Dagny-Ann Sandnes, Guido Werner Alves, Ole-Bjørn Tysnes and Charalampos Tzoulis

Biomolecules 2022, 12(6), 747; https://doi.org/10.3390/biom12060747 - 25 May 2022

Cited by 6 | Viewed by 2008

Abstract

Idiopathic Parkinson’s disease (iPD) is characterized by degeneration of the dopaminergic substantia nigra pars compacta (SNc), typically in the presence of Lewy pathology (LP) and mitochondrial respiratory complex I (CI) deficiency. LP is driven by α-synuclein aggregation, morphologically evolving from early punctate inclusions to Lewy bodies (LBs). The relationship between α-synuclein aggregation and CI deficiency in iPD is poorly understood. While studies in models suggest they are causally linked, observations in human SNc show that LBs preferentially occur in CI intact neurons. Since LBs are end-results of α-synuclein aggregation, we hypothesized that the relationship between LP and CI deficiency may be better reflected in neurons with early-stage α-synuclein pathology. Using quadruple immunofluorescence in SNc tissue from eight iPD subjects, we assessed the relationship between neuronal CI or CIV deficiency and early or late forms of LP. In agreement with previous findings, we did not observe CI-negative neurons with late LP. In contrast, early LP showed a significant predilection for CI-negative neurons (p = 6.3 × 10⁻⁵). CIV deficiency was not associated with LP. Our findings indicate that early α-syn aggregation is associated with CI deficiency in iPD, and suggest a double-hit mechanism, where neurons exhibiting both these pathologies are selectively lost. Full article

(This article belongs to the Special Issue Recent Advances in α-Synuclein Neurobiology in Health and Disease)

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10 pages, 999 KiB

Open AccessEditor’s ChoiceArticle

Plasma Extracellular Vesicle α-Synuclein Level in Patients with Parkinson’s Disease

by Chen-Chih Chung, Lung Chan, Jia-Hung Chen, Yi-Chieh Hung and Chien-Tai Hong

Biomolecules 2021, 11(5), 744; https://doi.org/10.3390/biom11050744 - 17 May 2021

Cited by 14 | Viewed by 2850

Abstract

Background: The most established pathognomonic protein of Parkinson’s disease (PD), α-synuclein, is extensively investigated for disease diagnosis and prognosis; however, investigations into whether the free form of α-synuclein in the blood functions as a PD biomarker have not been fruitful. Extracellular vesicles (EVs) secreted from cells and present in blood transport molecules are novel platforms for biomarker identification. In blood EVs, α-synuclein originates predominantly from the brain without the interference of the blood–brain barrier. The present study investigated the role of plasma EV-borne α-synuclein as a biomarker of PD. Methods: Patients with mild to moderate stages of PD (n = 116) and individuals without PD (n = 46) were recruited to serve as the PD study group and the control group, respectively. Plasma EVs were isolated, and immunomagnetic reduction–based immunoassay was used to assess EV α-synuclein levels. Conventional statistical analysis was performed using SPSS 25.0, and p < 0.05 was considered significant. Results: Compared with controls, we observed significantly lower plasma EV α-synuclein levels in the patients with PD (PD: 56.0 ± 3.7 fg/mL vs. control: 74.5 ± 4.3 fg/mL, p = 0.009), and the significance remained after adjustment for age and sex. Plasma EV α-synuclein levels in the patients with PD did not correlate with age, disease duration, Part I and II scores of the Unified Parkinson’s Disease Rating Scale (UPDRS), or the Mini-Mental State Examination scores. However, such levels were significantly correlated with UPDRS Part III score, which assesses motor dysfunction. Furthermore, the severity of akinetic-rigidity symptoms, but not tremor, was inversely associated with plasma EV α-synuclein level. Conclusion: Plasma EV α-synuclein was significantly different between the control and PD group and was associated with akinetic-rigidity symptom severity in patients with PD. This study corroborates the possible diagnostic and subtyping roles of plasma EV α-synuclein in patients with PD, and it further provides a basis for this protein’s clinical relevance and feasibility as a PD biomarker. Full article

(This article belongs to the Special Issue Recent Advances in α-Synuclein Neurobiology in Health and Disease)

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Review

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21 pages, 1201 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Exosomes in Alpha-Synucleinopathies: Propagators of Pathology or Potential Candidates for Nanotherapeutics?

by Panagiota Mavroeidi, Maria Vetsi, Dimitra Dionysopoulou and Maria Xilouri

Biomolecules 2022, 12(7), 957; https://doi.org/10.3390/biom12070957 - 8 Jul 2022

Cited by 9 | Viewed by 2961

Abstract

The pathological accumulation of alpha-synuclein governs the pathogenesis of neurodegenerative disorders, such as Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, collectively termed alpha-synucleinopathies. Alpha-synuclein can be released in the extracellular space, partly via exosomes, and this extracellular protein pool may contribute to disease progression by facilitating the spread of pathological alpha-synuclein or activating immune cells. The content of exosomes depends on their origin and includes specific proteins, lipids, functional mRNAs and various non-coding RNAs. Given their ability to mediate intercellular communication via the transport of multilevel information, exosomes are considered to be transporters of toxic agents. Beyond neurons, glial cells also release exosomes, which may contain inflammatory molecules and this glia-to-neuron or neuron-to-glia transmission of exosomal alpha-synuclein may contribute to the propagation of pathology and neuroinflammation throughout the brain. In addition, as their content varies as per their originating and recipient cells, these vesicles can be utilized as a diagnostic biomarker for early disease detection, whereas targeted exosomes may be used as scaffolds to deliver therapeutic agents into the brain. This review summarizes the current knowledge regarding the role of exosomes in the progression of alpha-synuclein-related pathology and their potential use as biomarkers and nanotherapeutics in alpha-synucleinopathies. Full article

(This article belongs to the Special Issue Recent Advances in α-Synuclein Neurobiology in Health and Disease)

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15 pages, 1548 KiB

Open AccessReview

Extracellular Alpha-Synuclein: Mechanisms for Glial Cell Internalization and Activation

by Cecilia Chavarría, Rodrigo Ivagnes and José M. Souza

Biomolecules 2022, 12(5), 655; https://doi.org/10.3390/biom12050655 - 30 Apr 2022

Cited by 15 | Viewed by 3598

Abstract

Alpha-synuclein (α-syn) is a small protein composed of 140 amino acids and belongs to the group of intrinsically disordered proteins. It is a soluble protein that is highly expressed in neurons and expressed at low levels in glial cells. The monomeric protein aggregation process induces the formation of oligomeric intermediates and proceeds towards fibrillar species. These α-syn conformational species have been detected in the extracellular space and mediate consequences on surrounding neurons and glial cells. In particular, higher-ordered α-syn aggregates are involved in microglial and oligodendrocyte activation, as well as in the induction of astrogliosis. These phenomena lead to mitochondrial dysfunction, reactive oxygen and nitrogen species formation, and the induction of an inflammatory response, associated with neuronal cell death. Several receptors participate in cell activation and/or in the uptake of α-syn, which can vary depending on the α-syn aggregated state and cell types. The receptors involved in this process are of outstanding relevance because they may constitute potential therapeutic targets for the treatment of PD and related synucleinopathies. This review article focuses on the mechanism associated with extracellular α-syn uptake in glial cells and the consequent glial cell activation that contributes to the neuronal death associated with synucleinopathies. Full article

(This article belongs to the Special Issue Recent Advances in α-Synuclein Neurobiology in Health and Disease)

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12 pages, 1017 KiB

Open AccessReview

Lipotoxicity Downstream of α-Synuclein Imbalance: A Relevant Pathomechanism in Synucleinopathies?

by Arati Tripathi, Saranna Fanning and Ulf Dettmer

Biomolecules 2022, 12(1), 40; https://doi.org/10.3390/biom12010040 - 28 Dec 2021

Cited by 4 | Viewed by 2068

Abstract

Neuronal loss in Parkinson’s disease and related brain diseases has been firmly linked to the abundant neuronal protein α-synuclein (αS). However, we have gained surprisingly little insight into how exactly αS exerts toxicity in these diseases. Hypotheses of proteotoxicity, disturbed vesicle trafficking, mitochondrial dysfunction and other toxicity mechanisms have been proposed, and it seems possible that a combination of different mechanisms may drive pathology. A toxicity mechanism that has caught increased attention in the recent years is αS-related lipotoxicity. Lipotoxicity typically occurs in a cell when fatty acids exceed the metabolic needs, triggering a flux into harmful pathways of non-oxidative metabolism. Genetic and experimental approaches have revealed a significant overlap between lipid storage disorders, most notably Gaucher’s disease, and synucleinopathies. There is accumulating evidence for lipid aberrations causing synuclein misfolding as well as for αS excess and misfolding causing lipid aberration. Does that mean the key problem in synucleinopathies is lipotoxicity, the accumulation of harmful lipid species or alteration in lipid equilibrium? Here, we review the existing literature in an attempt to get closer to an answer. Full article

(This article belongs to the Special Issue Recent Advances in α-Synuclein Neurobiology in Health and Disease)

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