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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: closed (31 December 2021) | Viewed by 20227

Special Issue Editors


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Guest Editor
School of Pharmacy and Medical Sciences, Griffith University, Southport, QLD 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
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Guest Editor
Department of Molecular Medicine and USF Health Byrd Alzheimer's Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
Interests: protein physics; protein folding; protein misfolding; intrinsically disordered proteins; protein function; protein interactions
Special Issues, Collections and Topics 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 (3 papers)

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Research

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20 pages, 4964 KiB  
Article
ATP13A2 Regulates Cellular α-Synuclein Multimerization, Membrane Association, and Externalization
by Jianmin Si, Chris Van den Haute, Evy Lobbestael, Shaun Martin, Sarah van Veen, Peter Vangheluwe and Veerle Baekelandt
Int. J. Mol. Sci. 2021, 22(5), 2689; https://doi.org/10.3390/ijms22052689 - 7 Mar 2021
Cited by 15 | Viewed by 5088
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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Review

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32 pages, 4924 KiB  
Review
Ferritinophagy and α-Synuclein: Pharmacological Targeting of Autophagy to Restore Iron Regulation in Parkinson’s Disease
by Matthew K. Boag, Angus Roberts, Vladimir N. Uversky, Linlin Ma, Des R. Richardson and Dean L. Pountney
Int. J. Mol. Sci. 2022, 23(4), 2378; https://doi.org/10.3390/ijms23042378 - 21 Feb 2022
Cited by 11 | Viewed by 4008
Abstract
A major hallmark of Parkinson’s disease (PD) is the fatal destruction of dopaminergic neurons within the substantia nigra pars compacta. This event is preceded by the formation of Lewy bodies, which are cytoplasmic inclusions composed of α-synuclein protein aggregates. A triad contribution [...] Read more.
A major hallmark of Parkinson’s disease (PD) is the fatal destruction of dopaminergic neurons within the substantia nigra pars compacta. This event is preceded by the formation of Lewy bodies, which are cytoplasmic inclusions composed of α-synuclein protein aggregates. A triad contribution of α-synuclein aggregation, iron accumulation, and mitochondrial dysfunction plague nigral neurons, yet the events underlying iron accumulation are poorly understood. Elevated intracellular iron concentrations up-regulate ferritin expression, an iron storage protein that provides cytoprotection against redox stress. The lysosomal degradation pathway, autophagy, can release iron from ferritin stores to facilitate its trafficking in a process termed ferritinophagy. Aggregated α-synuclein inhibits SNARE protein complexes and destabilizes microtubules to halt vesicular trafficking systems, including that of autophagy effectively. The scope of this review is to describe the physiological and pathological relationship between iron regulation and α-synuclein, providing a detailed understanding of iron metabolism within nigral neurons. The underlying mechanisms of autophagy and ferritinophagy are explored in the context of PD, identifying potential therapeutic targets for future investigation. Full article
(This article belongs to the Special Issue Alpha-Synuclein in Neurodegeneration)
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23 pages, 1235 KiB  
Review
The Prion-Like Spreading of Alpha-Synuclein in Parkinson’s Disease: Update on Models and Hypotheses
by Asad Jan, Nádia Pereira Gonçalves, Christian Bjerggaard Vaegter, Poul Henning Jensen and Nelson Ferreira
Int. J. Mol. Sci. 2021, 22(15), 8338; https://doi.org/10.3390/ijms22158338 - 3 Aug 2021
Cited by 51 | Viewed by 9732
Abstract
The pathological aggregation of the presynaptic protein α-synuclein (α-syn) and propagation through synaptically coupled neuroanatomical tracts is increasingly thought to underlie the pathophysiological progression of Parkinson’s disease (PD) and related synucleinopathies. Although the precise molecular mechanisms responsible for the spreading of pathological α-syn [...] Read more.
The pathological aggregation of the presynaptic protein α-synuclein (α-syn) and propagation through synaptically coupled neuroanatomical tracts is increasingly thought to underlie the pathophysiological progression of Parkinson’s disease (PD) and related synucleinopathies. Although the precise molecular mechanisms responsible for the spreading of pathological α-syn accumulation in the CNS are not fully understood, growing evidence suggests that de novo α-syn misfolding and/or neuronal internalization of aggregated α-syn facilitates conformational templating of endogenous α-syn monomers in a mechanism reminiscent of prions. A refined understanding of the biochemical and cellular factors mediating the pathological neuron-to-neuron propagation of misfolded α-syn will potentially elucidate the etiology of PD and unravel novel targets for therapeutic intervention. Here, we discuss recent developments on the hypothesis regarding trans-synaptic propagation of α-syn pathology in the context of neuronal vulnerability and highlight the potential utility of novel experimental models of synucleinopathies. Full article
(This article belongs to the Special Issue Alpha-Synuclein in Neurodegeneration)
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