The Deubiquitinase OTUD1 Involves In Parkinson’s Disease By Promoting Degradation Of Parkin

Parkinson’s Disease(PD)is a neurodegenerative disease caused by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain.The pathogenesis of PD is still unclear,and a large number of studies have shown that PD is associated with hereditary and environmental factors.PD is divided into familial PD and sporadic PD according to its different pathogenesis.Among them,abnormal mutation of parkin gene,encoding E3 ubiquitin ligase Parkin,is the most common cause of autosomal recessive PD.Since Parkin-mediated mitochondrial autophagy plays a great role in maintaining mitochondrial homeostasis,in addition to participating in familial PD,dysfunction of Parkin protein can also lead to sporadic PD.Parkin ubiquitination is closely associated with its activity and stability.The ubiquitin modification is a reversible process,which can be hydrolyzed and cleaved the ubiquitin chains from substrate protein by deubiquitinase.However,the deubiquitinases involved in Parkin regulation remain incompletely understood.Here,we screened OTUD1,a deubiquitination enzyme acting on Parkin,from the OTU family.OTUD1 directly interacted with Parkin and deubiquitinated Parkin relying on its own enzyme activity,and negatively regulated the protein level of Parkin leading to reducing Parkin’s recruitment to damaged mitochondria.Further studies indicated that OTUD1 reduced Parkin protein levels by promoting its autophagic lysosomal degradation through removing the polyubiquitin chains on Parkin.Moreover,we further confirmed that OTUD1 deficiency reduced MPTP-induced damage to dopaminergic neurons accompanied with the improvement of the motor ability of mice in vivo,which may be related to the up-regulation of Parkin protein level.In summary,our study clarified that the deubiquitination enzyme OTUD1,as an important regulator of Parkin,promoted the degradation of Parkin by promoting its autophagic lysosomal degradation through deubiquitination modification,and involved in the development of Parkinson’s Disease.This study enriched the regulatory mechanism of Parkin protein stability,provided a new idea for revealing the pathogenesis of PD,and a potential target for clinical prevention and treatment of PD.