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Special Issue "Alpha-Synuclein in Neurodegeneration"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 31 May 2021.

Special Issue Editors

Dr. Dean L. Pountney
E-Mail Website
Guest Editor
School of Medical Science, Griffith University, Gold Coast 4222, Australia
Interests: Parkinson's disease; multiple system atrophy; dementia with Lewy bodies; alpha-synuclein; small ubiquitin-like modifier (SUMO); metallothionein; neuroinflammation; calcium; copper; autophagy
Dr. Vladimir N. Uversky
grade E-Mail Website
Guest Editor
Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States
Interests: proteon physics; protein folding; protein structure; protein function; protein misfolding; protein aggregation; intrinsically disordered proteins; proteinopathies; proteinaceous membrane-less organelles; liquid–liquid phase transitions
Special Issues and Collections in MDPI journals

Special Issue Information

Dear colleagues,

α-Synuclein plays a pivotal role in the development of multiple neurodegenerative diseases that are known collectively as synucleinopathies and include Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. For many years, research has focused on the formation of intracellular aggregates of protein as the principal causative link to neurodegeneration. Recent studies have revealed many diverse intra- and extracellular neurotoxic interactions, encompassing imbalance in proteostatic systems, metal ion dyshomeostasis, liquid–liquid phase separation, secretory pathway, and mitochondrial dynamics. Although α-synuclein is expressed in multiple different cell types throughout the body, the normal functions of the protein at the neuronal pre-synapse regulating neurotransmitter vesicle trafficking have received much attention and no doubt contribute to the loss of function effects. Emerging data also implicate extracellular roles of α-synuclein as a secreted protein or processed peptide in neuroinflammation and by interacting with other disease-linked extracellular proteins, such as tau and Aβ. Central to the normal and pathological activities of α-synuclein is the dynamic nature of the protein that is modulated by calcium-binding, interaction with various partners, and by a variety of post-translational modifications. Self-association of α-synuclein in oligomeric, pre-fibrillar, and fibrillar forms provides platforms for the interaction of α-synuclein with a growing array of proteins, lipids, small molecules, and ions. Altogether, α-synuclein, with its spatiotemporal structural heterogeneity and multifunctionality represents an important example of the protein structure-function continuum concept. The design of novel neuroprotective and ameliorative therapies requires a comprehensive understanding of the α-synuclein interactome network in order to tackle both the initiation and progression of disease processes. In this Special Issue, we hope that investigators will join together in exploring and integrating the current knowledge to stimulate future inquiry towards the end of disease mitigation.

Dr. Dean L. Pountney
Dr. Vladimir N. Uversky
Guest Editors

Manuscript Submission Information

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Keywords

  • Alpha-synuclein
  • Parkinson’s disease
  • Dementia with Lewy bodies
  • Multiple system atrophy
  • Proteostasis
  • Protein misfolding
  • Disordered proteins
  • Mitochondria
  • Autophagy
  • Neuroinflammation

Published Papers (1 paper)

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Research

Open AccessArticle
ATP13A2 Regulates Cellular α-Synuclein Multimerization, Membrane Association, and Externalization
Int. J. Mol. Sci. 2021, 22(5), 2689; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052689 - 07 Mar 2021
Viewed by 787
Abstract
ATP13A2, a late endo-/lysosomal polyamine transporter, is implicated in a variety of neurodegenerative diseases, including Parkinson’s disease and Kufor–Rakeb syndrome, an early-onset atypical form of parkinsonism. Loss-of-function mutations in ATP13A2 result in lysosomal deficiency as a consequence of impaired lysosomal export of the [...] Read more.
ATP13A2, a late endo-/lysosomal polyamine transporter, is implicated in a variety of neurodegenerative diseases, including Parkinson’s disease and Kufor–Rakeb syndrome, an early-onset atypical form of parkinsonism. Loss-of-function mutations in ATP13A2 result in lysosomal deficiency as a consequence of impaired lysosomal export of the polyamines spermine/spermidine. Furthermore, accumulating evidence suggests the involvement of ATP13A2 in regulating the fate of α-synuclein, such as cytoplasmic accumulation and external release. However, no consensus has yet been reached on the mechanisms underlying these effects. Here, we aimed to gain more insight into how ATP13A2 is linked to α-synuclein biology in cell models with modified ATP13A2 activity. We found that loss of ATP13A2 impairs lysosomal membrane integrity and induces α-synuclein multimerization at the membrane, which is enhanced in conditions of oxidative stress or exposure to spermine. In contrast, overexpression of ATP13A2 wildtype (WT) had a protective effect on α-synuclein multimerization, which corresponded with reduced αsyn membrane association and stimulation of the ubiquitin-proteasome system. We also found that ATP13A2 promoted the secretion of α-synuclein through nanovesicles. Interestingly, the catalytically inactive ATP13A2 D508N mutant also affected polyubiquitination and externalization of α-synuclein multimers, suggesting a regulatory function independent of the ATPase and transport activity. In conclusion, our study demonstrates the impact of ATP13A2 on α-synuclein multimerization via polyamine transport dependent and independent functions. Full article
(This article belongs to the Special Issue Alpha-Synuclein in Neurodegeneration)
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