Cooperative inhibition of SNARE-mediated vesicle fusion by α-synuclein monomers and oligomers

Yoo, Gyeongji; Yeou, Sanghun; Son, Jung Bae; Shin, Yeon‐Kyun; Lee, Nam Ki

doi:10.1038/s41598-021-90503-0

Cited by 23 publications

(18 citation statements)

References 65 publications

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“…Experimental evidence has indicated that proteins Rab3A [ 72 ], Rab8b, Rab11a, and Rab13 [ 82 ] promote the clearance of α-synuclein aggregates, thereby preventing α-synuclein-induced toxicity. Additionally, α-synuclein monomers and oligomers cooperatively inhibit neuronal SNARE-mediated vesicle fusion and at sub-micromolar concentrations, α-synuclein monomers increased the fusion inhibition by α-synuclein oligomers [ 83 ]. The researchers developed a model to block oligomer binding and thus reduce toxicity during vesicle fusion.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Aggregated Alpha Synuclein on Synaptic and Axonal Proteins in Parkinson’s Disease—A Systematic Review

Murphy

McKernan

2022

Biomolecules

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α-synuclein is a core component of Lewy bodies, one of the pathological hallmarks of Parkinson’s disease. Aggregated α-synuclein can impair both synaptic functioning and axonal transport. However, understanding the pathological role that α-synuclein plays at a cellular level is complicated as existing findings are multifaceted and dependent on the mutation, the species, and the quantity of the protein that is involved. This systematic review aims to stratify the research findings to develop a more comprehensive understanding of the role of aggregated α-synuclein on synaptic and axonal proteins in Parkinson’s disease models. A literature search of the PubMed, Scopus, and Web of Science databases was conducted and a total of 39 studies were included for analysis. The review provides evidence for the dysregulation or redistribution of synaptic and axonal proteins due to α-synuclein toxicity. However, due to the high quantity of variables that were used in the research investigations, it was challenging to ascertain exactly what effect α-synuclein has on the expression of the proteins. A more standardized experimental approach regarding the variables that are employed in future studies is crucial so that existing literature can be consolidated. New research involving aggregated α-synuclein at the synapse and regarding axonal transport could be advantageous in guiding new treatment solutions.

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Section: Discussionmentioning

confidence: 99%

The Effect of Aggregated Alpha Synuclein on Synaptic and Axonal Proteins in Parkinson’s Disease—A Systematic Review

Murphy

McKernan

2022

Biomolecules

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“…Studies in neuronal systems demonstrated interaction of aSyn and SNARE-complex (soluble N-ethylmaleimide-sensitive-factor attachment receptor) molecules mediating synaptic vesicle fusion and neurotransmitter release [84,85]. Here, aSyn appears to play an important role as a regulator for complex formation and SNARE-dependent vesicle fusion by promoting vesicle docking [84][85][86]. Additionally, Scott et al identified SNARE proteins that are associated with melanocytic cell membranes [87,88] and showed that melanosomes contain the SNARE accessory protein called alpha-SNAP [87,88].…”

Section: Discussionmentioning

confidence: 99%

Alpha-Synuclein and Its Role in Melanocytes

Rachinger

Mittag

Böhme-Schäfer

et al. 2022

Cells

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Pigmentation is an important process in skin physiology and skin diseases and presumably also plays a role in Parkinson’s disease (PD). In PD, alpha-Synuclein (aSyn) has been shown to be involved in the pigmentation of neurons. The presynaptic protein is intensively investigated for its pathological role in PD, but its physiological function remains unknown. We hypothesized that aSyn is both involved in melanocytic differentiation and melanosome trafficking processes. We detected a strong expression of aSyn in human epidermal melanocytes (NHEMs) and observed its regulation in melanocytic differentiation via the microphthalmia-associated transcription factor (MITF), a central regulator of differentiation. Moreover, we investigated its role in pigmentation by performing siRNA experiments but found no effect on the total melanin content. We discovered a localization of aSyn to melanosomes, and further analysis of aSyn knockdown revealed an important role in melanocytic morphology and a reduction in melanosome release. Additionally, we found a reduction of transferred melanosomes in co-culture experiments of melanocytes and keratinocytes but no complete inhibition of melanosome transmission. In summary, this study highlights a novel physiological role of aSyn in melanocytic morphology and its so far unknown function in the pigment secretion in melanocytes.

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“…Both α-syn monomers and α-syn oligomers induce the clustering of SV. The α-syn mutant T44P/A89P with reduced lipid-binding affinity reduces the clustering of SV by α-syn oligomers in vitro [167].…”

Section: In Vitro Studiesmentioning

confidence: 98%

Alpha-Synuclein and Lipids: The Elephant in the Room?

Sarchione

Marchand

Taymans

et al. 2021

Cells

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Since the initial identification of alpha-synuclein (α-syn) at the synapse, numerous studies demonstrated that α-syn is a key player in the etiology of Parkinson’s disease (PD) and other synucleinopathies. Recent advances underline interactions between α-syn and lipids that also participate in α-syn misfolding and aggregation. In addition, increasing evidence demonstrates that α-syn plays a major role in different steps of synaptic exocytosis. Thus, we reviewed literature showing (1) the interplay among α-syn, lipids, and lipid membranes; (2) advances of α-syn synaptic functions in exocytosis. These data underscore a fundamental role of α-syn/lipid interplay that also contributes to synaptic defects in PD. The importance of lipids in PD is further highlighted by data showing the impact of α-syn on lipid metabolism, modulation of α-syn levels by lipids, as well as the identification of genetic determinants involved in lipid homeostasis associated with α-syn pathologies. While questions still remain, these recent developments open the way to new therapeutic strategies for PD and related disorders including some based on modulating synaptic functions.

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Cooperative inhibition of SNARE-mediated vesicle fusion by α-synuclein monomers and oligomers

Cited by 23 publications

References 65 publications

The Effect of Aggregated Alpha Synuclein on Synaptic and Axonal Proteins in Parkinson’s Disease—A Systematic Review

The Effect of Aggregated Alpha Synuclein on Synaptic and Axonal Proteins in Parkinson’s Disease—A Systematic Review

Alpha-Synuclein and Its Role in Melanocytes

Alpha-Synuclein and Lipids: The Elephant in the Room?

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