Deubiquitylase OTUD3 prevents Parkinson’s disease through stabilizing iron regulatory protein 2

Abstract

Iron deposits are neuropathological hallmark of Parkinson’s disease (PD). Iron regulatory protein 2 (IRP2) is a key factor in regulating brain iron homeostasis. Although two ubiquitin ligases that promote IRP2 degradation have been identified, the deubiquitylase for stabilization of IRP2 in PD remains undefined. Here, we report OTUD3 (OTU domain-containing protein 3) functions as a deubiquitylase for IRP2, interacts with IRP2 in the cytoplasm, de-polyubiquitylates, and stabilizes IRP2 protein in an iron-independent manner. Depletion of OTUD3 results in a disorder of iron metabolism. OTUD3 knockout mice display nigral iron accumulation, motor deficits, and nigrostriatal dopaminergic neurodegeneration, which resembles the pathology of PD. Consistently, decreased levels of OTUD3 are detected in transgenic PD mice expressing A53T mutant of human α-synuclein. Five single nucleotide polymorphism mutations of OTUD3 are present in cases of sporadic PD or controls, although no significant associations of OTUD3 SNPs with sporadic PD are detected. Taken together, these findings demonstrate that OTUD3 is a bona fide deubiquitylase for IRP2 and plays a critical role in the nigral iron deposits in PD.

Deubiquitylase OTUD3 Mediates Endoplasmic Reticulum Stress through Regulating Fortilin Stability to Restrain Dopaminergic Neurons Apoptosis

“…OTUD3 has been identified as a tumor suppressor that is highly associated with tumorigenesis [ 41 , 42 ]. Our previous study found that OTUD3 knockout mice display motor deficits and nigrostriatal dopaminergic neurodegeneration, resembling the pathology of PD [ 5 ]. In the present study, we observed a significant increase in cell apoptosis after OTUD3 knockdown, consistent with our previous reports [ 5 ].…”

“…Our previous study found that OTUD3 knockout mice display motor deficits and nigrostriatal dopaminergic neurodegeneration, resembling the pathology of PD [ 5 ]. In the present study, we observed a significant increase in cell apoptosis after OTUD3 knockdown, consistent with our previous reports [ 5 ]. More and more evidence has shown that ER stress-induced apoptosis is an important cell death pathway for dopaminergic neurons [ 29 , 30 ].…”

“…Our data indicated that the ER stress caused by OTUD3 knockdown might be related the Fortilin expression. Our previous research showed that the iron content is increased in the SN of OTUD3 −/− mice [ 5 ], and abnormal iron metabolism can induce ER stress [ 24 ]. These evidences suggest that OTUD3 knockout may induce ER stress by reducing the expression of IRP2 protein and up-regulating the contents of iron in neurons.…”

“…Up to now, the pathogenesis of PD has not been fully elucidated. Our previous study has shown that OTU domain-containing protein 3 (OTUD3) prevents PD through stabilizing iron regulatory protein 2 (IRP2), and OTUD3 knockout mice showed dopaminergic neuronal death in the SN and Parkinsonian symptoms [ 5 ]. OTUD3 is a member of the OTU subfamily of the deubiquitinases (DUBs) family, which is highly correlated with tumorigenesis.…”

“…Our previous research demonstrated that the iron content in the SN of OTUD3 knockout mice increased by approximately two folds [ 5 ]. The abnormal iron metabolism can trigger ER stress [ 24 ].…”