한빛사논문
- 조회1,003
Minwoo Baek1,5, Yun-Jeong Choe1,5, Sylvie Bannwarth2, JiHye Kim1, Swati Maitra1, Gerald W. Dorn II3, J. Paul Taylor4, Veronique Paquis-Flucklinger2 & Nam Chul Kim1,*
1Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Duluth, MN, USA. 2Inserm U1081, CNRS UMR7284, IRCAN, Université Côte d’Azur, CHU de Nice, Nice, France. 3Center for Pharmacogenomics, Washington University School of Medicine, St. Louis,
MO, USA. 4Howard Hughes Medical Institute and Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA.
5These authors contributed equally: Minwoo Baek, Yun-Jeong Choe.
*Corresponding author
Abstract
Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) can cause amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). However, the underlying mechanisms are unclear. Here, we generate CHCH10S59L-mutant Drosophila melanogaster and HeLa cell lines to model CHCHD10-associated ALS-FTD. The CHCHD10S59L mutation results in cell toxicity in several tissues and mitochondrial defects. CHCHD10S59L independently affects the TDP-43 and PINK1 pathways. CHCHD10S59L expression increases TDP-43 insolubility and mitochondrial translocation. Blocking TDP-43 mitochondrial translocation with a peptide inhibitor reduced CHCHD10S59L-mediated toxicity. While genetic and pharmacological modulation of PINK1 expression and activity of its substrates rescues and mitigates the CHCHD10S59L-induced phenotypes and mitochondrial defects, respectively, in both Drosophila and HeLa cells. Our findings suggest that CHCHD10S59L-induced TDP-43 mitochondrial translocation and chronic activation of PINK1-mediated pathways result in dominant toxicity, providing a mechanistic insight into the CHCHD10 mutations associated with ALS-FTD.
논문정보
- Research article
- 2021년 03월 (BRIC 등록일 2021-04-14)
- 국외 연구진
- 생명과학 > 신경생물학
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