PRKN-linked familial Parkinson’s disease: cellular and molecular mechanisms of disease-linked variants

• Published in: Cellular and molecular life sciences : CMLS Vol. 81; no. 1; p. 223
• Main Authors: Clausen, Lene, Okarmus, Justyna, Voutsinos, Vasileios, Meyer, Morten, Lindorff-Larsen, Kresten, Hartmann-Petersen, Rasmus
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.12.2024; Springer Nature B.V
• Subjects: Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Control systems; Dopamine receptors; Drug development; genes; heterozygosity; homozygosity; Humans; Life Sciences; loss-of-function mutation; mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - pathology; Mitophagy; Mitophagy - genetics; Molecular modelling; Movement disorders; Neurodegenerative diseases; Parkin protein; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; protein value; Proteins; Quality control; Review; Software; Substantia nigra; therapeutics; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Ubiquitination - genetics; MAVE; Ubiquitin; PRKN; Protein degradation; Protein stability; DMS; Protein quality control; PARK2; Mitochondria; Protein folding; VUS; AR-JP; Parkinson’s disease; Proteasome
• ISSN: 1420-682X; 1420-9071; 1420-9071
• DOI: 10.1007/s00018-024-05262-8

Parkinson’s disease (PD) is a common and incurable neurodegenerative disorder that arises from the loss of dopaminergic neurons in the substantia nigra and is mainly characterized by progressive loss of motor function. Monogenic familial PD is associated with highly penetrant variants in specific genes, notably the PRKN gene, where homozygous or compound heterozygous loss-of-function variants predominate. PRKN encodes Parkin, an E3 ubiquitin-protein ligase important for protein ubiquitination and mitophagy of damaged mitochondria. Accordingly, Parkin plays a central role in mitochondrial quality control but is itself also subject to a strict protein quality control system that rapidly eliminates certain disease-linked Parkin variants. Here, we summarize the cellular and molecular functions of Parkin, highlighting the various mechanisms by which PRKN gene variants result in loss-of-function. We emphasize the importance of high-throughput assays and computational tools for the clinical classification of PRKN gene variants and how detailed insights into the pathogenic mechanisms of PRKN gene variants may impact the development of personalized therapeutics.