α-Synuclein A30P decreases neurodegeneration and increases synaptic vesicle release probability in CSPα-null mice

• α-SynucleinhA30P overexpression slows neurodegeneration of motor nerve terminals.
• Synaptic vesicle release probability is restored in CSPα KO mice by α-synucleinhA30P.
• α-SynucleinhA30P partially prevents active zones loss in CSPα KO terminals.
• α-SynucleinhA30P partially restores the readily releasable pool size in CSPα KO mice.
• α-SynucleinhA30P has no effect on synaptic function or organization in WT mice.

α-Synuclein and Cysteine-string protein-α (CSPα) are presynaptic proteins that participate in the maintenance of synaptic function. Mutations or overexpression of the wild type form of α-synuclein have been related to Parkinson's disease, and CSPα mutations cause one type of neuronal ceroid lipofuscinosis. Both are adult-onset neurodegenerative diseases characterized by neuronal protein aggregations. Strikingly, while in mouse the lack of CSPα produces defective neurotransmission and neurodegeneration of motor terminals, blindness and early lethality, the moderate overexpression of wild-type α-synuclein fully rescues the CSPα-null phenotype. Contrarily, the overexpression of the mutated human α-synuclein A30P (α-synucleinhA30P) has much less effect in CSPα KO mice. To explore how the A30P mutation affects the neuroprotective function of α-synuclein we investigated synaptic structure and neurotransmission in motor nerve terminals of wild-type and CSPα-null mice transgenic for α-synucleinhA30P. We found that although α-synucleinhA30P did not fully prevent neurodegeneration, it significantly improved synaptic organization and function in CSPα-null mice by enhancing quantal content, release probability, synaptic vesicle content, active zone number, postsynaptic area, and microtubule appearance. These results demonstrate that α-synucleinhA30P is able to ameliorate synapse degeneration, despite its apparent lack of functionality and its long-term pathogenic effects in neurons. These findings may help to understand better the dual function of α-synuclein regarding neurodegeneration.This article is part of the Special Issue entitled ‘The Synaptic Basis of Neurodegenerative Disorders’.