TY  - JOUR
AU  - Hoffmann, Christian
AU  - Sansevrino, Roberto
AU  - Morabito, Giuseppe
AU  - Logan, Chinyere
AU  - Vabulas, R Martin
AU  - Ulusoy, Ayse
AU  - Ganzella, Marcelo
AU  - Milovanovic, Dragomir
TI  - Synapsin Condensates Recruit alpha-Synuclein.
JO  - Journal of molecular biology
VL  - 433
IS  - 12
SN  - 0022-2836
CY  - Amsterdam [u.a.]
PB  - Elsevier
M1  - DZNE-2021-00363
SP  - 166961
PY  - 2021
AB  - 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.
KW  - Animals
KW  - Brain: cytology
KW  - Brain: metabolism
KW  - HEK293 Cells
KW  - Humans
KW  - Luminescent Proteins: genetics
KW  - Luminescent Proteins: metabolism
KW  - Macromolecular Substances: chemistry
KW  - Macromolecular Substances: metabolism
KW  - Microscopy, Confocal
KW  - Microscopy, Fluorescence
KW  - Rats
KW  - Synapsins: chemistry
KW  - Synapsins: metabolism
KW  - Synaptic Transmission
KW  - Synaptic Vesicles: metabolism
KW  - alpha-Synuclein: chemistry
KW  - alpha-Synuclein: metabolism
KW  - liquid-liquid phase separation (Other)
KW  - synapsin 1 (Other)
KW  - synaptic vesicles (Other)
KW  - synucleinopathies (Other)
KW  - α-synuclein (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:33774037
DO  - DOI:10.1016/j.jmb.2021.166961
UR  - https://pub.dzne.de/record/154773
ER  -