Therapeutic potential of Parkin and its regulation in Parkinson's disease

Abstract

Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the midbrain substantia nigra, resulting in motor and non-motor symptoms. While the exact etiology of PD remains elusive, a growing body of evidence suggests that dysfunction in the parkin protein plays a pivotal role in the pathogenesis of the disease. Parkin is an E3 ubiquitin ligase that ubiquitinates substrate proteins to control a number of crucial cellular processes including protein catabolism, immune response, and cellular apoptosis.While autosomal recessive mutations in the PARK2 gene, which codes for parkin, are linked to an inherited form of early-onset PD, heterozygous mutations in PARK2 have also been reported in the more commonly occurring sporadic PD cases. Impairment of parkin's E3 ligase activity is believed to play a pathogenic role in both familial and sporadic forms of PD.This article provides an overview of the current understanding of the mechanistic basis of parkin's E3 ligase activity, its major physiological role in controlling cellular functions, and how these are disrupted in familial and sporadic PD. The second half of the manuscript explores the currently available and potential therapeutic strategies targeting parkin structure and/or function in order to slow down or mitigate the progressive neurodegeneration in PD.

Keywords: Dopaminergic neurodegeneration; E3 ubiquitin ligase; Mitochondria; PARK2; Proteostasis.