Mitochondrial UQCRC1 mutations cause autosomal dominant parkinsonism with polyneuropathy

Chin Hsien Lin, Pei I. Tsai, Han Yi Lin, Nobutaka Hattori, Manabu Funayama, Beomseok Jeon, Kota Sato, Koji Abe, Yohei Mukai, Yuji Takahashi, Yuanzhe Li, Kenya Nishioka, Hiroyo Yoshino, Kensuke Daida, Meng Ling Chen, Jay Cheng, Cheng Yen Huang, Shiou Ru Tzeng, Yen Sheng Wu, Hsing Jung LaiHsin Hsi Tsai, Ruoh Fang Yen, Ni Chung Lee, Wen Chun Lo, Yu Chien Hung, Chih Chiang Chan, Yi Ci Ke, Chi Chao Chao, Sung Tsang Hsieh, Matthew Farrer, Ruey Meei Wu

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.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.

Original languageEnglish
Pages (from-to)3352-3373
Number of pages22
JournalBrain
Volume143
Issue number11
DOIs
Publication statusPublished - 2021

Keywords

  • Mitochondria
  • Parkinson's disease
  • Respiratory chain complex III
  • UQCRC1
  • Ubiquinol-cytochrome c reductase core protein

ASJC Scopus subject areas

  • Clinical Neurology

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