TY - JOUR

T1 - PRKN-linked familial Parkinson’s disease

T2 - cellular and molecular mechanisms of disease-linked variants

AU - Clausen, Lene

AU - Okarmus, Justyna

AU - Voutsinos, Vasileios

AU - Meyer, Morten

AU - Lindorff-Larsen, Kresten

AU - Hartmann-Petersen, Rasmus

N1 - Publisher Copyright: © The Author(s) 2024.

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

KW - AR-JP

KW - DMS

KW - MAVE

KW - Mitochondria

KW - PARK2

KW - Parkinson’s disease

KW - PRKN

KW - Proteasome

KW - Protein degradation

KW - Protein folding

KW - Protein quality control

KW - Protein stability

KW - Ubiquitin

KW - VUS

U2 - 10.1007/s00018-024-05262-8

DO - 10.1007/s00018-024-05262-8

M3 - Review

C2 - 38767677

AN - SCOPUS:85193678128

VL - 81

JO - Cellular and Molecular Life Sciences

JF - Cellular and Molecular Life Sciences

SN - 1420-682X

IS - 1

M1 - 223

ER -