Genetic inactivation of the USP19 deubiquitinase regulates a-synuclein ubiquitination and inhibits accumulation of Lewy body like aggregates in mice

作者：Lenka Schorova, Nathalie Bédard, Anouar Khayachi, Joao Bolivar-Pedroso, Hung-Hsiang Ho, Julie Huynh, Mikaela Piccirelli, Yifei Wang, Marie Plourde, Wen Luo, Esther del Cid‐Pellitero, Irina Shlaifer, Yihong Ye, Thomas M. Durcan, Simon S. Wing · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2022 · DOI：10.1101/2022.12.21.521125 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Alzheimer's disease research and treatments、Genetic Neurodegenerative Diseases

ABSTRACT The USP19 deubiquitinase is found in a locus associated with Parkinson’s Disease (PD), interacts with heat shock proteins and promotes secretion of a-synuclein (a-syn) through the misfolding associated protein secretion (MAPS) pathway. Since these processes might modulate the processing of a-syn aggregates during the progression of PD, we tested the effect of USP19 knockout (KO) in mice expressing the A53T mutation of a-syn and in whom a-syn preformed fibrils (PFF) had been injected in the striatum. Compared to WT, KO brains showed decreased accumulation of phospho-synuclein (pSyn) positive aggregates. The improved pathology was associated with less activation of microglia, higher levels of synaptic marker proteins and improved performance in a tail suspension test. Exposure of primary neurons from WT and KO mice to PFF in vitro also led to decreased accumulation of pSyn aggregates. KO did not affect uptake of PFF in the cultured neurons. It also did not affect the propagation of aggregates as assessed by exposing WT or KO neurons to PFF and measuring pSyn positive aggregates in non-exposed adjacent neurons separated using a microfluidics device. We conclude that USP19 instead modulates intracellular dynamics of aggregates. Indeed, at the early time following PFF injection when the number of pSyn positive neurons were similar in WT and KO brains, the KO neurons contained less aggregates. KO brain aggregates stained more intensely with anti-ubiquitin antibodies. Immun...