E3 ubiquitin-protein ligase parkin (PRKN) (PRKN)

The PRKN gene encodes the E3 ubiquitin-protein ligase parkin, a critical enzyme in the ubiquitin-proteasome system and mitochondrial quality control (Source 1.5.1, 1.5.4). Parkin functions primarily in mitophagy, the selective degradation of damaged mitochondria, by working in tandem with the kinase PINK1 to tag mitochondrial proteins with ubiquitin (Source 1.2.1, 1.2.3). Mutations in the PRKN gene are the most common cause of autosomal recessive juvenile Parkinson's disease (AR-JP), leading to the accumulation of dysfunctional mitochondria and the death of dopaminergic neurons (Source 1.3.3, 1.3.4). Beyond neurodegeneration, parkin acts as a tumor suppressor in various cancers, including glioblastoma and ovarian cancer, where its loss promotes uncontrolled cell division (Source 1.3.5, 1.5.1). It also plays a role in innate immunity by triggering the release of signaling molecules that activate immune cells to fight tumors (Source 1.3.5). Therapeutic strategies targeting parkin include the development of small-molecule activators to restore its ligase activity and gene therapy approaches for protein replacement (Source 1.4.1, 1.6.5). Additionally, indirect modulation of the parkin pathway via USP30 inhibitors is being explored to enhance mitophagy in neurodegenerative conditions (Source 1.4.4, 1.6.1). Research into parkin activators like BIO-2007817 aims to rescue the function of mutant parkin proteins in patients with early-onset Parkinson's (Source 1.4.3). Monitoring biomarkers such as phospho-ubiquitin (pS65-Ub) and parkin mRNA levels is essential for evaluating the efficacy of these emerging therapies (Source 1.1.1, 1.1.4). Overall, parkin represents a high-value target for disease-modifying treatments in both neurology and oncology (Source 1.4.1, 1.4.3).

Other names

ParkinPARK2Parkinson juvenile disease protein 2PDJAR-JPParkinson disease protein 2

Allosteric activation of E3 ligase activity and gene replacement therapy