Regulation of MCCC1 expression by a Parkinson’s disease-associated intronic variant: implications for pathogenesis
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by dopaminergic neuron loss and α-synuclein aggregation. While some familial cases result from single-gene mutations, most are sporadic, involving complex genetic and environmental interactions. Among PD risk loci identified through genome-wide association studies, MCCC1 encodes a mitochondrial enzyme essential for leucine catabolism; however, the causal variant remains unclear. Here, we investigated whether the intronic variant rs12637471 regulates MCCC1 mRNA expression and influences PD risk. Postmortem brain analysis revealed significantly elevated MCCC1 mRNA levels in G-allele carriers, consistent with peripheral tissue eQTL data from GTEx. Using CRISPR/Cas9-edited induced pluripotent stem cells, we generated isogenic lines differing only at rs12637471 and observed increased MCCC1 expression in G-allele dopaminergic neurons. Given MCCC1's mitochondrial role, its dysregulation may impact mitochondrial homeostasis, autophagy, or inflammation, potentially contributing to PD pathogenesis.
Authors
- Shunsaku Sogabe
- Ryusaku Matsumoto (ORCID: https://orcid.org/0000-0002-7191-5326)
- Shigeo Murayama (ORCID: https://orcid.org/0000-0001-9709-5242)
- Tatsushi Toda (ORCID: https://orcid.org/0000-0002-0717-1123)
- Kazuhiro Kobayashi (ORCID: https://orcid.org/0000-0001-7801-147X)
- Yusuke Ogasahara
- Yukio Ando (ORCID: https://orcid.org/0000-0001-7115-9105)
- Wataru Satake
- Takashi Aoi (ORCID: https://orcid.org/0000-0002-3963-5922)
- Motoi Kanagawa (ORCID: https://orcid.org/0000-0003-0984-6398)
- Mariko Taniguchi‐Ikeda (ORCID: https://orcid.org/0000-0002-1607-400X)
- Pei-Chieng Cha (ORCID: https://orcid.org/0000-0002-5718-2824)
- Hiroko Nakano (ORCID: https://orcid.org/0000-0002-4912-1802)
Institutions
- Kyoto University (JP)
- University of Tokyo Hospital (JP)
- National Cerebral and Cardiovascular Center (JP)
- Fujita Health University Hospital (JP)
- Tokyo Metropolitan Institute of Gerontology (JP)
- Ehime University (JP)
- Kobe University (JP)
- The University of Tokyo (JP)
- The University of Osaka (JP)
Publication Details
- Journal
- Journal of Human Genetics
- Published
- 2025-04-11
- DOI
- https://doi.org/10.1038/s10038-025-01335-z
- Citations
- 2
- Primary Topic
- CRISPR and Genetic Engineering
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Japan Agency for Medical Research and Development
- Ministry of Health, Labour and Welfare
- University of Tokyo
- Japan Society for the Promotion of Science