Alpha-Synuclein is Involved in DYT1 Dystonia Striatal Synaptic Dysfunction

Background: The neuronal protein alphasynuclein (alpha-Syn) is crucially involved in Parkinson's disease pathophysiology. Intriguingly, torsinA (TA), the protein causative of DYT1 dystonia, has been found to accumulate in Lewy bodies and to interact with alpha-Syn. Both proteins act as molecular chaperones and control synaptic machinery. Despite such evidence, the role of alpha-Syn in dystonia has never been investigated. Objective: We explored whether alpha-Syn and Nethylmaleimide sensitive fusion attachment protein receptor proteins (SNAREs), that are known to be modulated by alpha-Syn, may be involved in DYT1 dystonia synaptic dysfunction. Methods: We used electrophysiological and biochemical techniques to study synaptic alterations in the dorsal striatum of the Tor1a(+/Delta gag) mouse model of DYT1 dystonia. Results: In the Tor1a(+/Delta gag) DYT1 mutant mice, we found a significant reduction of alpha-Syn levels in whole striata, mainly involving glutamatergic corticostriatal terminals. Strikingly, the striatal levels of the vesicular SNARE VAMP-2, a direct alpha-Syn interactor, and of the transmembrane SNARE synaptosome-associated protein 23 (SNAP-23), that promotes glutamate synaptic vesicles release, were markedly decreased in mutant mice. Moreover, we detected an impairment of miniature glutamatergic postsynaptic currents (mEPSCs) recorded from striatal spiny neurons, in parallel with a decreased asynchronous release obtained by measuring quantal EPSCs (gEPSCs), which highlight a robust alteration in release probability. Finally, we also observed a significant reduction of TA striatal expression in alpha-Syn null mice. Conclusions: Our data demonstrate an unprecedented relationship between TA and alpha-Syn, and reveal that alpha-Syn and SNAREs alterations characterize the synaptic dysfunction underlying DYT1 dystonia. (C) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Automated summary

This study reveals the relationship between TA and alpha-Syn and demonstrates that alterations in alpha-Syn and SNAREs characterize the synaptic dysfunction underlying DYT1 dystonia.