PRKN-linked familial Parkinson’s disease: cellular and molecular mechanisms of disease-linked variants
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PRKN-linked familial Parkinson’s disease : cellular and molecular mechanisms of disease-linked variants. / Clausen, Lene; Okarmus, Justyna; Voutsinos, Vasileios; Meyer, Morten; Lindorff-Larsen, Kresten; Hartmann-Petersen, Rasmus.
In: Cellular and Molecular Life Sciences, Vol. 81, No. 1, 223, 2024.Research output: Contribution to journal › Review › Research › peer-review
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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 -
ID: 392986904