Mitochondrial UQCRC1 mutations cause autosomal dominant parkinsonism with polyneuropathy
Journal
Brain
Journal Volume
143
Journal Volume
143
Journal Issue
11
Journal Issue
11
Start Page
3352
End Page
3373
ISSN
0006-8950
Date Issued
2021
Author(s)
Tsai, Pei-I
Lin, Han-Yi
Hattori, Nobutaka
Funayama, Manabu
Jeon, Beomseok
Sato, Kota
Abe, Koji
Mukai, Yohei
Takahashi, Yuji
Li, Yuanzhe
Nishioka, Kenya
Yoshino, Hiroyo
Daida, Kensuke
Chen, Meng-Ling
Cheng, Jay
Huang, Cheng-Yen
Wu, Yen-Sheng
Lo, Wen-Chun
Hung, Yu-Chien
Ke, Yi-Ci
Farrer, Matthew
Abstract
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.941A>C (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.931A>C (p.Ile311Leu) and an allele with concomitant splicing mutation (c.70-1G>A) 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.
Subjects
Parkinson’s disease; UQCRC1; mitochondria; respiratory chain complex III; ubiquinol-cytochrome c reductase core protein 1
SDGs
Type
journal article