|Title:||Mitochondrial UQCRC1 mutations cause autosomal dominant parkinsonism with polyneuropathy||Authors:||Tsai, Pei I.
Lin, Han Yi
Chen, Meng Ling
Huang, Cheng Yen
Wu, Yen Sheng
Lai, Hsing Jung
Tsai, Hsin Hsi
Lo, Wen Chun
Hung, Yu Chien
Ke, Yi Ci
|Keywords:||Mitochondria | Parkinson's disease | Respiratory chain complex III | Ubiquinol-cytochrome c reductase core protein | UQCRC1||Issue Date:||1-Jan-2021||Journal Volume:||143||Journal Issue:||11||Source:||Brain||Abstract:||
© 2020 Oxford University Press. All rights reserved. Parkinson's disease is a neurodegenerative disorder with a multifactorial aetiology. Nevertheless, the genetic predisposition in many families with multi-incidence disease remains unknown. This study aimed to identify novel genes that cause familial Parkinson's disease. Whole exome sequencing was performed in three affected members of the index family with a late-onset autosomal-dominant parkinsonism and polyneuropathy. We identified a novel heterozygous substitution c.941A4C (p.Tyr314Ser) in the mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene, which co-segregates with disease within the family. Additional analysis of 699 unrelated Parkinson's disease probands with autosomal-dominant Parkinson's disease and 1934 patients with sporadic Parkinson's disease revealed another two variants in UQCRC1 in the probands with familial Parkinson's disease, c.931A4C (p.Ile311Leu) and an allele with concomitant splicing mutation (c.70-1G4A) and a frameshift insertion (c.73_74insG, p.Ala25Glyfs∗27). All substitutions were absent in 1077 controls and the Taiwan Biobank exome database from healthy participants (n = 1517 exomes). We then assayed the pathogenicity of the identified rare variants using CRISPR/Cas9-based knock-in human dopaminergic SH-SY5Y cell lines, Drosophila and mouse models. Mutant UQCRC1 expression leads to neurite degeneration and mitochondrial respiratory chain dysfunction in SH-SY5Y cells. UQCRC1 p.Tyr314Ser knock-in Drosophila and mouse models exhibit age-dependent locomotor defects, dopaminergic neuronal loss, peripheral neuropathy, impaired respiratory chain complex III activity and aberrant mitochondrial ultrastructures in nigral neurons. Furthermore, intraperitoneal injection of levodopa could significantly improve the motor dysfunction in UQCRC1 p.Tyr314Ser mutant knock-in mice. Taken together, our in vitro and in vivo studies support the functional pathogenicity of rare UQCRC1 variants in familial parkinsonism. Our findings expand an additional link of mitochondrial complex III dysfunction in Parkinson's disease.
|Appears in Collections:||醫學院附設醫院 (臺大醫院)|
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.