Journal Article

DZNE-2021-00363

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Synapsin Condensates Recruit alpha-Synuclein.

Hoffmann, C. (First author)DZNE* ; Sansevrino, R. (First author)DZNE* ; Morabito, G.DZNE* ; Logan, C.DZNE* ; Vabulas, R. M. ; Ulusoy, A.DZNE* ; Ganzella, M. ; Milovanovic, D. (Last author)DZNE*

2021
Elsevier Amsterdam [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.jmb.2021.166961

Abstract: Neurotransmission relies on the tight spatial and temporal regulation of the synaptic vesicle (SV) cycle. Nerve terminals contain hundreds of SVs that form tight clusters. These clusters represent a distinct liquid phase in which one component of the phase are SVs and the other synapsin 1, a highly abundant synaptic protein. Another major family of disordered proteins at the presynapse includes synucleins, most notably α-synuclein. The precise physiological role of α-synuclein in synaptic physiology remains elusive, albeit its role has been implicated in nearly all steps of the SV cycle. To determine the effect of α-synuclein on the synapsin phase, we employ the reconstitution approach using natively purified SVs from rat brains and the heterologous cell system to generate synapsin condensates. We demonstrate that synapsin condensates recruit α-synuclein, and while enriched into these synapsin condensates, α-synuclein still maintains its high mobility. The presence of SVs enhances the rate of synapsin/α-synuclein condensation, suggesting that SVs act as catalyzers for the formation of synapsin condensates. Notably, at physiological salt and protein concentrations, α-synuclein alone is not able to cluster isolated SVs. Excess of α-synuclein disrupts the kinetics of synapsin/SV condensate formation, indicating that the molar ratio between synapsin and α-synuclein is important in assembling the functional condensates of SVs. Understanding the molecular mechanism of α-synuclein interactions at the nerve terminals is crucial for clarifying the pathogenesis of synucleinopathies, where α-synuclein, synaptic proteins and lipid organelles all accumulate as insoluble intracellular inclusions.

Keyword(s): Animals (MeSH) ; Brain: cytology (MeSH) ; Brain: metabolism (MeSH) ; HEK293 Cells (MeSH) ; Humans (MeSH) ; Luminescent Proteins: genetics (MeSH) ; Luminescent Proteins: metabolism (MeSH) ; Macromolecular Substances: chemistry (MeSH) ; Macromolecular Substances: metabolism (MeSH) ; Microscopy, Confocal (MeSH) ; Microscopy, Fluorescence (MeSH) ; Rats (MeSH) ; Synapsins: chemistry (MeSH) ; Synapsins: metabolism (MeSH) ; Synaptic Transmission (MeSH) ; Synaptic Vesicles: metabolism (MeSH) ; alpha-Synuclein: chemistry (MeSH) ; alpha-Synuclein: metabolism (MeSH) ; liquid-liquid phase separation ; synapsin 1 ; synaptic vesicles ; synucleinopathies ; α-synuclein

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Contributing Institute(s):

1. Molecular Neurobiology (AG Milovanovic ; AG Milovanovic)
2. Neurodegeneration and Neuroprotection in Parkinson´s Disease (AG Di Monte)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2021

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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