Role of Deubiquitinases in Parkinson’s Disease—Therapeutic Perspectives

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder that has been associated with mitochondrial dysfunction, oxidative stress, and defects in mitophagy as well as α-synuclein-positive inclusions, termed Lewy bodies (LBs), which are a common pathological hallmark in PD. Mitophagy is a process that maintains cellular health by eliminating dysfunctional mitochondria, and it is triggered by ubiquitination of mitochondrial-associated proteins—e.g., through the PINK1/Parkin pathway—which results in engulfment by the autophagosome and degradation in lysosomes. Deubiquitinating enzymes (DUBs) can regulate this process at several levels by deubiquitinating mitochondrial substrates and other targets in the mitophagic pathway, such as Parkin. Moreover, DUBs can affect α-synuclein aggregation through regulation of degradative pathways, deubiquitination of α-synuclein itself, and/or via co-localization with α-synuclein in inclusions. DUBs with a known association to PD are described in this paper, along with their function. Of interest, DUBs could be useful as novel therapeutic targets against PD through regulation of PD-associated defects.

Keywords

• neurodegeneration
• PARK2
• parkin
• mitochondria
• protein degradation
• ubiquitin proteasome system