Burre, J. | Search bioRxiv

bioRxiv2021

Lysosomal Exocytosis Releases Pathogenic α-Synuclein Species from Neurons

Considerable evidence supports the release of pathogenic aggregates of the neuronal protein -Synuclein (Syn) into the extracellular space. While this release is proposed to instigate the neuron-to-neuron transmission and spread of Syn pathology in synucleinopathies including Parkinsons disease, the molecular-cellular mechanism(s) remain unclear. Here we show that pathogenic species of Syn accumulate within neuronal lysosomes in mouse brains and primary neurons. We then find that neurons release these pathogenic Syn species via SNARE-dependent lysosomal exocytosis; proposing a central mechanism for exocytosis of aggregated and degradation-resistant proteins from neurons.

cell biology↗

bioRxiv2020

BETA- AND GAMMA-SYNUCLEINS MODULATE SYNAPTIC VESICLE-BINDING OF ALPHA-SYNUCLEIN

-Synuclein (Syn), {beta}-synuclein ({beta}Syn), and {gamma}-synuclein ({gamma}Syn) are abundantly expressed in the vertebrate nervous system. Syn functions in neurotransmitter release via binding to and clustering synaptic vesicles and chaperoning of SNARE-complex assembly. The functions of {beta}Syn and {gamma}Syn are unknown. Functional redundancy of the three synucleins and mutual compensation when one synuclein is deleted have been proposed, but with conflicting evidence. Here, we demonstrate that {beta}Syn and {gamma}Syn have a reduced affinity towards membranes compared to Syn, and that direct interaction of {beta}Syn or {gamma}Syn with Syn results in reduced membrane binding of Syn. Our data suggest that all three synucleins affect synapse function, but only Syn mediates the downstream function of vesicle clustering and SNARE-complex assembly, while {beta}Syn and {gamma}Syn modulate the activity of Syn through regulating its binding to synaptic vesicles.

neuroscience↗