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@ARTICLE{Hoffmann:154773,
author = {Hoffmann, Christian and Sansevrino, Roberto and Morabito,
Giuseppe and Logan, Chinyere and Vabulas, R Martin and
Ulusoy, Ayse and Ganzella, Marcelo and Milovanovic,
Dragomir},
title = {{S}ynapsin {C}ondensates {R}ecruit alpha-{S}ynuclein.},
journal = {Journal of molecular biology},
volume = {433},
number = {12},
issn = {0022-2836},
address = {Amsterdam [u.a.]},
publisher = {Elsevier},
reportid = {DZNE-2021-00363},
pages = {166961},
year = {2021},
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.},
keywords = {Animals / Brain: cytology / Brain: metabolism / HEK293
Cells / Humans / Luminescent Proteins: genetics /
Luminescent Proteins: metabolism / Macromolecular
Substances: chemistry / Macromolecular Substances:
metabolism / Microscopy, Confocal / Microscopy, Fluorescence
/ Rats / Synapsins: chemistry / Synapsins: metabolism /
Synaptic Transmission / Synaptic Vesicles: metabolism /
alpha-Synuclein: chemistry / alpha-Synuclein: metabolism /
liquid-liquid phase separation (Other) / synapsin 1 (Other)
/ synaptic vesicles (Other) / synucleinopathies (Other) /
α-synuclein (Other)},
cin = {AG Milovanovic ; AG Milovanovic / AG Di Monte},
ddc = {610},
cid = {I:(DE-2719)1813002 / I:(DE-2719)1013008},
pnm = {351 - Brain Function (POF4-351) / 352 - Disease Mechanisms
(POF4-352)},
pid = {G:(DE-HGF)POF4-351 / G:(DE-HGF)POF4-352},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:33774037},
doi = {10.1016/j.jmb.2021.166961},
url = {https://pub.dzne.de/record/154773},
}