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Scientific Reports Jun 2023The Parkinson's disease (PD) associated protein, alpha-synuclein (α-syn/SNCA), is highly expressed in aggressive melanomas. The goal of this study was to reveal...
The Parkinson's disease (PD) associated protein, alpha-synuclein (α-syn/SNCA), is highly expressed in aggressive melanomas. The goal of this study was to reveal possible mechanism(s) of α-syn involvement in melanoma pathogenesis. Herein, we asked whether α-syn modulates the expression of the pro-oncogenic adhesion molecules L1CAM and N-cadherin. We used two human melanoma cell lines (SK-MEL-28, SK-MEL-29), SNCA-knockout (KO) clones, and two human SH-SY5Y neuroblastoma cell lines. In the melanoma lines, loss of α-syn expression resulted in significant decreases in the expression of L1CAM and N-cadherin and concomitant significant decreases in motility. On average, there was a 75% reduction in motility in the four SNCA-KOs tested compared to control cells. Strikingly, comparing neuroblastoma SH-SY5Y cells that have no detectable α-syn to SH-SY5Y cells that stably express α-syn (SH/+αS), we found that expressing α-syn increased L1CAM and single-cell motility by 54% and 597%, respectively. The reduction in L1CAM level in SNCA-KO clones was not due to a transcriptional effect, rather we found that L1CAM is more efficiently degraded in the lysosome in SNCA-KO clones than in control cells. We propose that α-syn is pro-survival to melanoma (and possibly neuroblastoma) because it promotes the intracellular trafficking of L1CAM to the plasma membrane.
Topics: Humans; alpha-Synuclein; Cadherins; Melanoma; Neural Cell Adhesion Molecule L1; Neuroblastoma
PubMed: 37286800
DOI: 10.1038/s41598-023-36451-3 -
International Journal of Molecular... Mar 2024Synucleins are a family of proteins consisting of α, β, and γ synuclein (syn) [...].
Synucleins are a family of proteins consisting of α, β, and γ synuclein (syn) [...].
Topics: alpha-Synuclein; beta-Synuclein; gamma-Synuclein
PubMed: 38542197
DOI: 10.3390/ijms25063223 -
Acta Neuropathologica May 2023A 21-nucleotide duplication in one allele of SNCA was identified in a previously described disease with abundant α-synuclein inclusions that we now call juvenile-onset...
A 21-nucleotide duplication in one allele of SNCA was identified in a previously described disease with abundant α-synuclein inclusions that we now call juvenile-onset synucleinopathy (JOS). This mutation translates into the insertion of MAAAEKT after residue 22 of α-synuclein, resulting in a protein of 147 amino acids. Both wild-type and mutant proteins were present in sarkosyl-insoluble material that was extracted from frontal cortex of the individual with JOS and examined by electron cryo-microscopy. The structures of JOS filaments, comprising either a single protofilament, or a pair of protofilaments, revealed a new α-synuclein fold that differs from the folds of Lewy body diseases and multiple system atrophy (MSA). The JOS fold consists of a compact core, the sequence of which (residues 36-100 of wild-type α-synuclein) is unaffected by the mutation, and two disconnected density islands (A and B) of mixed sequences. There is a non-proteinaceous cofactor bound between the core and island A. The JOS fold resembles the common substructure of MSA Type I and Type II dimeric filaments, with its core segment approximating the C-terminal body of MSA protofilaments B and its islands mimicking the N-terminal arm of MSA protofilaments A. The partial similarity of JOS and MSA folds extends to the locations of their cofactor-binding sites. In vitro assembly of recombinant wild-type α-synuclein, its insertion mutant and their mixture yielded structures that were distinct from those of JOS filaments. Our findings provide insight into a possible mechanism of JOS fibrillation in which mutant α-synuclein of 147 amino acids forms a nucleus with the JOS fold, around which wild-type and mutant proteins assemble during elongation.
Topics: Humans; alpha-Synuclein; Synucleinopathies; Nigeria; Multiple System Atrophy; Mutation
PubMed: 36847833
DOI: 10.1007/s00401-023-02550-8 -
International Journal of Molecular... Jun 2022α-Synuclein is a protein with a molecular weight of 14.5 kDa and consists of 140 amino acids encoded by the gene. Missense mutations and gene duplications in the gene... (Review)
Review
α-Synuclein is a protein with a molecular weight of 14.5 kDa and consists of 140 amino acids encoded by the gene. Missense mutations and gene duplications in the gene cause hereditary Parkinson's disease. Highly phosphorylated and abnormally aggregated α-synuclein is a major component of Lewy bodies found in neuronal cells of patients with sporadic Parkinson's disease, dementia with Lewy bodies, and glial cytoplasmic inclusion bodies in oligodendrocytes with multiple system atrophy. Aggregated α-synuclein is cytotoxic and plays a central role in the pathogenesis of the above-mentioned synucleinopathies. In a healthy brain, most α-synuclein is unphosphorylated; however, more than 90% of abnormally aggregated α-synuclein in Lewy bodies of patients with Parkinson's disease is phosphorylated at Ser129, which is presumed to be of pathological significance. Several kinases catalyze Ser129 phosphorylation, but the role of phosphorylation enzymes in disease pathogenesis and their relationship to cellular toxicity from phosphorylation are not fully understood in α-synucleinopathy. Consequently, this review focuses on the pathogenic impact of α-synuclein phosphorylation and its kinases during the neurodegeneration process in α-synucleinopathy.
Topics: Humans; Lewy Bodies; Parkinson Disease; Phosphorylation; Synucleinopathies; alpha-Synuclein
PubMed: 35682892
DOI: 10.3390/ijms23116216 -
Cell Death & Disease Nov 2023Accumulation of α-synuclein aggregates in the substantia nigra pars compacta is central in the pathophysiology of Parkinson's disease, leading to the degeneration of...
Accumulation of α-synuclein aggregates in the substantia nigra pars compacta is central in the pathophysiology of Parkinson's disease, leading to the degeneration of dopaminergic neurons and the manifestation of motor symptoms. Although several PD models mimic the pathological accumulation of α-synuclein after overexpression, they do not allow for controlling and monitoring its aggregation. We recently generated a new optogenetic tool by which we can spatiotemporally control the aggregation of α-synuclein using a light-induced protein aggregation system. Using this innovative tool, we aimed to characterize the impact of α-synuclein clustering on mitochondria, whose activity is crucial to maintain neuronal survival. We observed that aggregates of α-synuclein transiently and dynamically interact with mitochondria, leading to mitochondrial depolarization, lower ATP production, mitochondrial fragmentation and degradation via cardiolipin externalization-dependent mitophagy. Aggregation of α-synuclein also leads to lower mitochondrial content in human dopaminergic neurons and in mouse midbrain. Interestingly, overexpression of α-synuclein alone did not induce mitochondrial degradation. This work is among the first to clearly discriminate between the impact of α-synuclein overexpression and aggregation on mitochondria. This study thus represents a new framework to characterize the role of mitochondria in PD.
Topics: Animals; Humans; Mice; alpha-Synuclein; Cardiolipins; Dopaminergic Neurons; Mitochondria; Mitophagy; Parkinson Disease; Substantia Nigra
PubMed: 37949858
DOI: 10.1038/s41419-023-06251-8 -
Molecular Neurobiology May 2021In protein aggregation disorders, we assume that, during the process of protein aggregation, different types of aggregated species (oligomers, protofibrils, fibrils,... (Review)
Review
In protein aggregation disorders, we assume that, during the process of protein aggregation, different types of aggregated species (oligomers, protofibrils, fibrils, etc.) are formed, some of which can be toxic to cells/tissues/organs. Recent evidence from numerous studies in cell and animal models of disease suggest that oligomeric species of different proteins might be more toxic that the larger, fibrillar forms. However, we still lack definitive data on the nature of the toxic species, mostly due to our inability to detect and define the various protein species that form as protein aggregate. The terms used are often broad and do not capture inter-laboratory variation in protocols and methods used for the characterization of aggregates. Even antibody-based methods can be ambiguous, as antibodies are delicate tools. Therefore, systematic and interdisciplinary studies are essential in order to guide future developments in the field.
Topics: Antibodies; Humans; Protein Aggregation, Pathological; alpha-Synuclein
PubMed: 33411246
DOI: 10.1007/s12035-020-02269-7 -
Gut Microbes Dec 2023Alpha-synuclein (α-syn) pathology is the hallmark of Parkinson's disease (PD). The leucine-rich repeat kinase 2 () gene is a major-effect risk gene for sporadic PD...
Alpha-synuclein (α-syn) pathology is the hallmark of Parkinson's disease (PD). The leucine-rich repeat kinase 2 () gene is a major-effect risk gene for sporadic PD (sPD). However, what environmental factors may trigger the formation of α-syn pathology in carriers of risk variants are still unknown. Here, we report that a markedly increased abundance of (. ) in the intestinal microbiota was detected in risk variant(R1628P or G2385R) carriers with sPD compared with carriers without sPD. Animal experiments showed that . administration triggered pathological α-syn accumulation in the colon and spread to the brain via the gut-brain axis in R1628P mice, due to the co-occurrence of variant-induced inhibition of α-syn autophagic degradation and increased phosphorylation of α-syn caused by curli in . -derived extracellular vesicles. Fecal microbiota transplantation (FMT) effectively ameliorated motor deficits and α-syn pathology in R1628P mice. Our findings elaborate on the mechanism that triggers α-syn pathology in R1628P mice, and highlight a novel gene-environment interaction pattern in risk variants. Even more importantly, the findings reveal the interplay between the specific risk gene and the matched environmental factors triggers the initiation of α-syn pathology in sPD.
Topics: Mice; Animals; Parkinson Disease; Mice, Transgenic; alpha-Synuclein; Escherichia coli; Gastrointestinal Microbiome
PubMed: 38010914
DOI: 10.1080/19490976.2023.2276296 -
Journal of Parkinson's Disease 2023Oligomerization and aggregation of misfolded forms of α-synuclein are believed to be key molecular mechanisms in Parkinson's disease (PD) and other synucleinopathies,... (Review)
Review
Oligomerization and aggregation of misfolded forms of α-synuclein are believed to be key molecular mechanisms in Parkinson's disease (PD) and other synucleinopathies, so extensive research has attempted to understand these processes. Among diverse post-translational modifications that impact α-synuclein aggregation, glycation may take place at several lysine sites and modify α-synuclein oligomerization, toxicity, and clearance. The receptor for advanced glycation end products (RAGE) is considered a key regulator of chronic neuroinflammation through microglial activation in response to advanced glycation end products, such as carboxy-ethyl-lysine, or carboxy-methyl-lysine. The presence of RAGE in the midbrain of PD patients has been reported in the last decades and this receptor was proposed to have a role in sustaining PD neuroinflammation. However, different PD animal models demonstrated that RAGE is preferentially expressed in neurons and astrocytes, while recent evidence demonstrated that fibrillar, non-glycated α-synuclein binds to RAGE. Here, we summarize the available data on α-synuclein glycation and RAGE in the context of PD, and discuss about the questions yet to be answered that may increase our understanding of the molecular bases of PD and synucleinopathies.
Topics: Animals; alpha-Synuclein; Lysine; Maillard Reaction; Neuroinflammatory Diseases; Parkinson Disease; Receptor for Advanced Glycation End Products; Synucleinopathies
PubMed: 37270812
DOI: 10.3233/JPD-230070 -
Proceedings of the National Academy of... Jun 2023α-Synuclein accumulates in Lewy bodies, and this accumulation is a pathological hallmark of Parkinson's disease (PD). Previous studies have indicated a causal role of...
α-Synuclein accumulates in Lewy bodies, and this accumulation is a pathological hallmark of Parkinson's disease (PD). Previous studies have indicated a causal role of α-synuclein in the pathogenesis of PD. However, the molecular and cellular mechanisms of α-synuclein toxicity remain elusive. Here, we describe a novel phosphorylation site of α-synuclein at T64 and the detailed characteristics of this post-translational modification. T64 phosphorylation was enhanced in both PD models and human PD brains. T64D phosphomimetic mutation led to distinct oligomer formation, and the structure of the oligomer was similar to that of α-synuclein oligomer with A53T mutation. Such phosphomimetic mutation induced mitochondrial dysfunction, lysosomal disorder, and cell death in cells and neurodegeneration in vivo, indicating a pathogenic role of α-synuclein phosphorylation at T64 in PD.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Phosphorylation; Lewy Bodies; Brain
PubMed: 37252975
DOI: 10.1073/pnas.2214652120 -
Biomolecules Jan 2022Alpha-synucleinopathies include Parkinson's disease, dementia with Lewy bodies, pure autonomic failure and multiple system atrophy. These are all progressive... (Review)
Review
Alpha-synucleinopathies include Parkinson's disease, dementia with Lewy bodies, pure autonomic failure and multiple system atrophy. These are all progressive neurodegenerative diseases that are characterized by pathological misfolding and accumulation of the protein alpha-synuclein (αsyn) in neurons, axons or glial cells in the brain, but also in other organs. The abnormal accumulation and propagation of pathogenic αsyn across the autonomic connectome is associated with progressive loss of neurons in the brain and peripheral organs, resulting in motor and non-motor symptoms. To date, no cure is available for synucleinopathies, and therapy is limited to symptomatic treatment of motor and non-motor symptoms upon diagnosis. Recent advances using passive immunization that target different αsyn structures show great potential to block disease progression in rodent studies of synucleinopathies. However, passive immunotherapy in clinical trials has been proven safe but less effective than in preclinical conditions. Here we review current achievements of passive immunotherapy in animal models of synucleinopathies. Furthermore, we propose new research strategies to increase translational outcome in patient studies, (1) by using antibodies against immature conformations of pathogenic αsyn (monomers, post-translationally modified monomers, oligomers and protofibrils) and (2) by focusing treatment on body-first synucleinopathies where damage in the brain is still limited and effective immunization could potentially stop disease progression by blocking the spread of pathogenic αsyn from peripheral organs to the brain.
Topics: Animals; Humans; Immunization, Passive; Lewy Bodies; Models, Animal; Synucleinopathies; alpha-Synuclein
PubMed: 35204668
DOI: 10.3390/biom12020168