Sogabe Shunsaku, Nakano Hiroko, Ogasahara Yusuke, Cha Pei-Chieng, Ando Yuko, Taniguchi-Ikeda Mariko, Matsumoto Ryusaku, Kanagawa Motoi, Kobayashi Kazuhiro, Murayama Shigeo, Aoi Takashi, Toda Tatsushi, Satake Wataru
Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Hyogo, 650-0017, Japan.
Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovascular Center, Suita, Osaka, 564-8565, Japan.
J Hum Genet. 2025 Apr 11. doi: 10.1038/s10038-025-01335-z.
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.
帕金森病（PD）是一种常见的神经退行性疾病，其特征为多巴胺能神经元丧失和α-突触核蛋白聚集。虽然一些家族性病例由单基因突变引起，但大多数是散发性的，涉及复杂的遗传和环境相互作用。在通过全基因组关联研究确定的PD风险基因座中，MCCC1编码一种对亮氨酸分解代谢至关重要的线粒体酶；然而，致病变异仍不清楚。在这里，我们研究了内含子变异rs12637471是否调节MCCC1 mRNA表达并影响PD风险。死后大脑分析显示，G等位基因携带者的MCCC1 mRNA水平显著升高，这与来自GTEx的外周组织eQTL数据一致。使用CRISPR/Cas9编辑的诱导多能干细胞，我们生成了仅在rs12637471处不同的同基因系，并观察到G等位基因多巴胺能神经元中MCCC1表达增加。鉴于MCCC1的线粒体作用，其失调可能影响线粒体稳态、自噬或炎症，可能导致PD发病机制。
