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  • Deubiquitylase OTUD3 prevents Parkinson's disease through stabilizing iron regulatory protein 2.

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

Cell death & disease (2022-05-01)
Fengju Jia, Hongchang Li, Qian Jiao, Chaonan Li, Lin Fu, Chunping Cui, Hong Jiang, Lingqiang Zhang
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-OTUD3 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
Sigma-Aldrich
Anti-SLC40A1 antibody produced in rabbit, purified immunoglobulin, buffered aqueous solution