ATPase Thorase Deficiency Causes α-Synucleinopathy and Parkinson's Disease-like Behavior

Parkinson's disease (PD) is one of the most common neurodegenerative diseases and is pathologically characterized by alpha-synucleinopathy, which is harmful to dopaminergic neurons. However, the underlying mechanisms and pathogenesis of PD remain unclear. The AAA + ATPase Thorase was identified as being essential for neuroprotection and synaptic plasticity by regulating the AMPA receptor trafficking. Here, we found that conditional knockout of Thorase resulted in motor behaviors indicative of neurodegeneration. Genetic deletion of Thorase exacerbated phenotypes of alpha-synucleinopathy in a familial PD-like A53T mouse model, whereas overexpression of Thorase prevented alpha-syn accumulation in vivo. Biochemical and cell cultures studies presented here suggest that Thorase interacts with alpha-syn and regulates the degradation of ubiquitinated alpha-syn. Thorase deficiency promotes alpha-syn aggregation in primary cultured neurons. The discoveries in this study provide us with a further understanding of the pathogenesis of alpha-synucleinopathies including PD.

Automated summary

This study reveals the critical role of the AAA + ATPase Thorase in neuroprotection and synaptic plasticity. It interacts with alpha-synuclein and regulates its degradation, providing further insights into the pathogenesis of alpha-synucleinopathies including Parkinson's disease.