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Synucleins in Neurodegeneration
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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 15513

Special Issue Editors

Dr. Dean L. Pountney

E-Mail Website
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
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Vladimir N. Uversky

grade E-Mail Website
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 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

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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

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Published Papers (6 papers)

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Research

69 pages, 20793 KiB  
Article
Exploring Intrinsic Disorder in Human Synucleins and Associated Proteins
by Sriya Reddy Venati and Vladimir N. Uversky
Int. J. Mol. Sci. 2024, 25(15), 8399; https://doi.org/10.3390/ijms25158399 - 1 Aug 2024
Viewed by 880
Abstract
In this work, we explored the intrinsic disorder status of the three members of the synuclein family of proteins—α-, β-, and γ-synucleins—and showed that although all three human synucleins are highly disordered, the highest levels of disorder are observed in γ-synuclein. Our analysis [...] Read more.
In this work, we explored the intrinsic disorder status of the three members of the synuclein family of proteins—α-, β-, and γ-synucleins—and showed that although all three human synucleins are highly disordered, the highest levels of disorder are observed in γ-synuclein. Our analysis of the peculiarities of the amino acid sequences and modeled 3D structures of the human synuclein family members revealed that the pathological mutations A30P, E46K, H50Q, A53T, and A53E associated with the early onset of Parkinson’s disease caused some increase in the local disorder propensity of human α-synuclein. A comparative sequence-based analysis of the synuclein proteins from various evolutionary distant species and evaluation of their levels of intrinsic disorder using a set of commonly used bioinformatics tools revealed that, irrespective of their origin, all members of the synuclein family analyzed in this study were predicted to be highly disordered proteins, indicating that their intrinsically disordered nature represents an evolutionary conserved and therefore functionally important feature. A detailed functional disorder analysis of the proteins in the interactomes of the human synuclein family members utilizing a set of commonly used disorder analysis tools showed that the human α-synuclein interactome has relatively higher levels of intrinsic disorder as compared with the interactomes of human β- and γ- synucleins and revealed that, relative to the β- and γ-synuclein interactomes, α-synuclein interactors are involved in a much broader spectrum of highly diversified functional pathways. Although proteins interacting with three human synucleins were characterized by highly diversified functionalities, this analysis also revealed that the interactors of three human synucleins were involved in three common functional pathways, such as the synaptic vesicle cycle, serotonergic synapse, and retrograde endocannabinoid signaling. Taken together, these observations highlight the critical importance of the intrinsic disorder of human synucleins and their interactors in various neuronal processes. Full article
(This article belongs to the Special Issue Synucleins in Neurodegeneration)
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13 pages, 2878 KiB  
Article
Alpha-Synuclein Interaction with UBL3 Is Upregulated by Microsomal Glutathione S-Transferase 3, Leading to Increased Extracellular Transport of the Alpha-Synuclein under Oxidative Stress
by Jing Yan, Tomoaki Kahyo, Hengsen Zhang, Yashuang Ping, Chi Zhang, Shuyun Jiang, Qianqing Ji, Rafia Ferdous, Md. Shoriful Islam, Soho Oyama, Shuhei Aramaki, Tomohito Sato, Mst. Afsana Mimi, Md. Mahmudul Hasan and Mitsutoshi Setou
Int. J. Mol. Sci. 2024, 25(13), 7353; https://doi.org/10.3390/ijms25137353 - 4 Jul 2024
Cited by 2 | Viewed by 1225
Abstract
Aberrant aggregation of misfolded alpha-synuclein (α-syn), a major pathological hallmark of related neurodegenerative diseases such as Parkinson’s disease (PD), can translocate between cells. Ubiquitin-like 3 (UBL3) is a membrane-anchored ubiquitin-fold protein and post-translational modifier. UBL3 promotes protein sorting into small extracellular vesicles (sEVs) [...] Read more.
Aberrant aggregation of misfolded alpha-synuclein (α-syn), a major pathological hallmark of related neurodegenerative diseases such as Parkinson’s disease (PD), can translocate between cells. Ubiquitin-like 3 (UBL3) is a membrane-anchored ubiquitin-fold protein and post-translational modifier. UBL3 promotes protein sorting into small extracellular vesicles (sEVs) and thereby mediates intercellular communication. Our recent studies have shown that α-syn interacts with UBL3 and that this interaction is downregulated after silencing microsomal glutathione S-transferase 3 (MGST3). However, how MGST3 regulates the interaction of α-syn and UBL3 remains unclear. In the present study, we further explored this by overexpressing MGST3. In the split Gaussia luciferase complementation assay, we found that the interaction between α-syn and UBL3 was upregulated by MGST3. While Western blot and RT-qPCR analyses showed that silencing or overexpression of MGST3 did not significantly alter the expression of α-syn and UBL3, the immunocytochemical staining analysis indicated that MGST3 increased the co-localization of α-syn and UBL3. We suggested roles for the anti-oxidative stress function of MGST3 and found that the effect of MGST3 overexpression on the interaction between α-syn with UBL3 was significantly rescued under excess oxidative stress and promoted intracellular α-syn to extracellular transport. In conclusion, our results demonstrate that MGST3 upregulates the interaction between α-syn with UBL3 and promotes the interaction to translocate intracellular α-syn to the extracellular. Overall, our findings provide new insights and ideas for promoting the modulation of UBL3 as a therapeutic agent for the treatment of synucleinopathy-associated neurodegenerative diseases. Full article
(This article belongs to the Special Issue Synucleins in Neurodegeneration)
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13 pages, 2778 KiB  
Article
Alpha-Synuclein and GM1 Ganglioside Co-Localize in Neuronal Cytosol Leading to Inverse Interaction—Relevance to Parkinson’s Disease
by Ranjeet Kumar, Suman Chowdhury and Robert Ledeen
Int. J. Mol. Sci. 2024, 25(6), 3323; https://doi.org/10.3390/ijms25063323 - 15 Mar 2024
Viewed by 1550
Abstract
Research on GM1 ganglioside and its neuroprotective role in Parkinson’s disease (PD), particularly in mitigating the aggregation of α-Synuclein (aSyn), is well established across various model organisms. This essential molecule, GM1, is intimately linked to preventing aSyn aggregation, and its deficiency is believed [...] Read more.
Research on GM1 ganglioside and its neuroprotective role in Parkinson’s disease (PD), particularly in mitigating the aggregation of α-Synuclein (aSyn), is well established across various model organisms. This essential molecule, GM1, is intimately linked to preventing aSyn aggregation, and its deficiency is believed to play a key role in the initiation of PD. In our current study, we attempted to shed light on the cytosolic interactions between GM1 and aSyn based on previous reports demonstrating gangliosides and monomeric aSyn to be present in neuronal cytosol. Native-PAGE and Western blot analysis of neuronal cytosol from mouse brains demonstrated the presence of both GM1 and monomeric aSyn in the neuronal cytosol of normal mouse brain. To demonstrate that an adequate level of GM1 prevents the aggregation of aSyn, we used NG108-15 and SH-SY5Y cells with and without treatment of 1-phenyl-2-palmitoyl-3-morpholino-1-propanol (PPMP), which inhibits the synthesis/expression of GM1. Cells treated with PPMP to reduce GM1 expression showed a significant increase in the formation of aggregated aSyn compared to untreated cells. We thus demonstrated that sufficient GM1 prevents the aggregation of aSyn. For this to occur, aSyn and GM1 must show proximity within the neuron. The present study provides evidence for such co-localization in neuronal cytosol, which also facilitates the inverse interaction revealed in studies with the two cell types above. This adds to the explanation of how GM1 prevents the aggregation of aSyn and onset of Parkinson’s disease. Full article
(This article belongs to the Special Issue Synucleins in Neurodegeneration)
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30 pages, 7239 KiB  
Article
Damage to the Locus Coeruleus Alters the Expression of Key Proteins in Limbic Neurodegeneration
by Francesca Biagioni, Michela Ferrucci, Gloria Lazzeri, Mariarosaria Scioli, Alessandro Frati, Stefano Puglisi-Allegra and Francesco Fornai
Int. J. Mol. Sci. 2024, 25(6), 3159; https://doi.org/10.3390/ijms25063159 - 9 Mar 2024
Cited by 1 | Viewed by 1878
Abstract
The present investigation was designed based on the evidence that, in neurodegenerative disorders, such as Alzheimer’s dementia (AD) and Parkinson’s disease (PD), damage to the locus coeruleus (LC) arising norepinephrine (NE) axons (LC-NE) is documented and hypothesized to foster the onset and progression [...] Read more.
The present investigation was designed based on the evidence that, in neurodegenerative disorders, such as Alzheimer’s dementia (AD) and Parkinson’s disease (PD), damage to the locus coeruleus (LC) arising norepinephrine (NE) axons (LC-NE) is documented and hypothesized to foster the onset and progression of neurodegeneration within target regions. Specifically, the present experiments were designed to assess whether selective damage to LC-NE axons may alter key proteins involved in neurodegeneration within specific limbic regions, such as the hippocampus and piriform cortex, compared with the dorsal striatum. To achieve this, a loss of LC-NE axons was induced by the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) in C57 Black mice, as assessed by a loss of NE and dopamine-beta-hydroxylase within target regions. In these experimental conditions, the amount of alpha-synuclein (alpha-syn) protein levels were increased along with alpha-syn expressing neurons within the hippocampus and piriform cortex. Similar findings were obtained concerning phospho-Tau immunoblotting. In contrast, a decrease in inducible HSP70-expressing neurons and a loss of sequestosome (p62)-expressing cells, along with a loss of these proteins at immunoblotting, were reported. The present data provide further evidence to understand why a loss of LC-NE axons may foster limbic neurodegeneration in AD and limbic engagement during PD. Full article
(This article belongs to the Special Issue Synucleins in Neurodegeneration)
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13 pages, 2327 KiB  
Article
Inhibition of Ubiquitin-Specific Protease-13 Improves Behavioral Performance in Alpha-Synuclein Expressing Mice
by Xiaoguang Liu, Kaluvu Balaraman, Ciarán C. Lynch, Michaeline Hebron, Priya Ketankumar Shah, Shicheng Hu, Max Stevenson, Christian Wolf and Charbel Moussa
Int. J. Mol. Sci. 2022, 23(15), 8131; https://doi.org/10.3390/ijms23158131 - 23 Jul 2022
Cited by 6 | Viewed by 3129
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
by Zhengcun Wu, Xiuao Zhang, Zhangqiong Huang and Kaili Ma
Int. J. Mol. Sci. 2022, 23(6), 3394; https://doi.org/10.3390/ijms23063394 - 21 Mar 2022
Cited by 39 | Viewed by 5480
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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