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Synucleins 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 2023) | Viewed by 7536

Special Issue Editors

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
Special Issues, Collections and Topics in MDPI journals
Department of Molecular Medicine, USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, MDC07, Tampa, FL 33612, USA
Interests: intrinsically disordered proteins; protein folding; protein misfolding; partially folded proteins; protein aggregation; protein structure; protein function; protein stability; protein biophysics; protein bioinformatics; conformational diseases; protein–ligand interactions; protein–protein interactions; liquid-liquid phase transitions
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 suggest the extracellular role of α-synuclein as a secreted protein or processed peptide in neuroinflammation that interacts 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 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. Furthermore, the potential roles of other members of synuclein family, i.e., β- and γ-synucleins, in normal and pathological processes are becoming obvious. The design of novel neuroprotective and ameliorative therapies requires a comprehensive understanding of the interactome network of the synuclein family members 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 our current knowledge to stimulate future inquiry towards the goal of disease mitigation.

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

Manuscript Submission Information

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Keywords

  • α-synuclein
  • β-synuclein
  • γ-Synuclein
  • Parkinson’s disease
  • dementia with Lewy bodies
  • multiple system atrophy
  • proteostasis
  • protein misfolding
  • protein–protein interactions
  • posttranslational modifications
  • disordered proteins
  • mitochondria
  • autophagy
  • neuroinflammation

Published Papers (2 papers)

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Research

13 pages, 2327 KiB  
Article
Inhibition of Ubiquitin-Specific Protease-13 Improves Behavioral Performance in Alpha-Synuclein Expressing Mice
Int. J. Mol. Sci. 2022, 23(15), 8131; https://doi.org/10.3390/ijms23158131 - 23 Jul 2022
Cited by 3 | Viewed by 2312
Abstract
Ubiquitin-Specific Protease-13 (USP13) promotes protein de-ubiquitination. USP13 levels are upregulated in post-mortem Parkinson’s disease, whereas USP13 knockdown via shRNA reduces alpha-synuclein levels in animal models. We studied the role of USP13 in knockout mice expressing lentiviral human alpha-synuclein and investigated the impact of [...] Read more.
Ubiquitin-Specific Protease-13 (USP13) promotes protein de-ubiquitination. USP13 levels are upregulated in post-mortem Parkinson’s disease, whereas USP13 knockdown via shRNA reduces alpha-synuclein levels in animal models. We studied the role of USP13 in knockout mice expressing lentiviral human alpha-synuclein and investigated the impact of a small molecule inhibitor of USP13, BK50118-C, on alpha-synuclein pathology and animal behavior. Alpha-synuclein was expressed unilaterally in substantia nigra (SN) of USP13 deficient mice that were treated with a daily intraperitoneal injection of 100 mg/kg BK50118-C or DMSO for four consecutive weeks, and behavioral and functional assays were performed. Wild-type USP13+/+ mice expressing lentiviral human alpha-synuclein showed motor and behavioral defects that were not seen in partially (USP13+/−) or completely (USP13−/−) deficient USP13 mice. BK50118-C displayed a wide and favorable therapeutic dose range in vivo. Treatment with BK50118-C significantly reduced ubiquitinated alpha-synuclein, increased dopamine levels, and improved motor and behavioral symptoms in wild-type (USP13+/+), but not USP13 deficient, mice. These data suggest that USP13 is critical to the neuropathology of alpha-synuclein, whereas a novel small molecule inhibitor of USP13 is a potential therapeutic agent of alpha-synucleinopathies. Full article
(This article belongs to the Special Issue Synucleins in Neurodegeneration)
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12 pages, 31415 KiB  
Article
SARS-CoV-2 Proteins Interact with Alpha Synuclein and Induce Lewy Body-like Pathology In Vitro
Int. J. Mol. Sci. 2022, 23(6), 3394; https://doi.org/10.3390/ijms23063394 - 21 Mar 2022
Cited by 25 | Viewed by 4239
Abstract
Growing cases of patients reported have shown a potential relationship between (severe acute respiratory syndrome coronavirus 2) SARS-CoV-2 infection and Parkinson’s disease (PD). However, it is unclear whether there is a molecular link between these two diseases. Alpha-synuclein (α-Syn), an aggregation-prone protein, is [...] Read more.
Growing cases of patients reported have shown a potential relationship between (severe acute respiratory syndrome coronavirus 2) SARS-CoV-2 infection and Parkinson’s disease (PD). However, it is unclear whether there is a molecular link between these two diseases. Alpha-synuclein (α-Syn), an aggregation-prone protein, is considered a crucial factor in PD pathology. In this study, bioinformatics analysis confirmed favorable binding affinity between α-Syn and SARS-CoV-2 spike (S) protein and nucleocapsid (N) protein, and direct interactions were further verified in HEK293 cells. The expression of α-Syn was upregulated and its aggregation was accelerated by S protein and N protein. It was noticed that SARS-CoV-2 proteins caused Lewy-like pathology in the presence of α-Syn overexpression. By confirming that SARS-CoV-2 proteins directly interact with α-Syn, our study offered new insights into the mechanism underlying the development of PD on the background of COVID-19. Full article
(This article belongs to the Special Issue Synucleins in Neurodegeneration)
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