TY - JOUR
T1 - The pathogenesis linked to coenzyme Q10 insufficiency in iPSC-derived neurons from patients with multiple-system atrophy
AU - Nakamoto, Fumiko Kusunoki
AU - Okamoto, Satoshi
AU - Mitsui, Jun
AU - Sone, Takefumi
AU - Ishikawa, Mitsuru
AU - Yamamoto, Yorihiro
AU - Kanegae, Yumi
AU - Nakatake, Yuhki
AU - Imaizumi, Kent
AU - Ishiura, Hiroyuki
AU - Tsuji, Shoji
AU - Okano, Hideyuki
N1 - Funding Information:
We thank Dr. Minoru S.H. Ko (Keio University), Dr. Kosuke Yusa (Wellcome Trust Sanger Institute) and Dr. Yumi Kanegae (Jikei University School of Medicine) for the materials provided. We thank Midori Nagase (Tokyo University of Technology) for her technical assistance in coenzyme Q10 and vitamin E measurements. We thank Dr. Koki Fujimori (Keio University) for his technical assistance and the helpful comments in analysis on IN Cell Analyzer. We thank Dr. Hajime Komano (Keio University) for the helpful comments and discussion. The research described in this study was supported by grants from the Program for Intractable Disease Research utilizing disease-specific iPS cells funded by the Japan Agency for Medical Research and Development (A-MED) to H.O.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Multiple-system atrophy (MSA) is a neurodegenerative disease characterized by autonomic failure with various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. We previously reported that functionally impaired variants of COQ2, which encodes an essential enzyme in the biosynthetic pathway of coenzyme Q10, are associated with MSA. Here, we report functional deficiencies in mitochondrial respiration and the antioxidative system in induced pluripotent stem cell (iPSC)-derived neurons from an MSA patient with compound heterozygous COQ2 mutations. The functional deficiencies were rescued by site-specific CRISPR/Cas9-mediated gene corrections. We also report an increase in apoptosis of iPSC-derived neurons from MSA patients. Coenzyme Q10 reduced apoptosis of neurons from the MSA patient with compound heterozygous COQ2 mutations. Our results reveal that cellular dysfunctions attributable to decreased coenzyme Q10 levels are related to neuronal death in MSA, particularly in patients with COQ2 variants, and may contribute to the development of therapy using coenzyme Q10 supplementation.
AB - Multiple-system atrophy (MSA) is a neurodegenerative disease characterized by autonomic failure with various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. We previously reported that functionally impaired variants of COQ2, which encodes an essential enzyme in the biosynthetic pathway of coenzyme Q10, are associated with MSA. Here, we report functional deficiencies in mitochondrial respiration and the antioxidative system in induced pluripotent stem cell (iPSC)-derived neurons from an MSA patient with compound heterozygous COQ2 mutations. The functional deficiencies were rescued by site-specific CRISPR/Cas9-mediated gene corrections. We also report an increase in apoptosis of iPSC-derived neurons from MSA patients. Coenzyme Q10 reduced apoptosis of neurons from the MSA patient with compound heterozygous COQ2 mutations. Our results reveal that cellular dysfunctions attributable to decreased coenzyme Q10 levels are related to neuronal death in MSA, particularly in patients with COQ2 variants, and may contribute to the development of therapy using coenzyme Q10 supplementation.
UR - http://www.scopus.com/inward/record.url?scp=85053721436&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85053721436&partnerID=8YFLogxK
U2 - 10.1038/s41598-018-32573-1
DO - 10.1038/s41598-018-32573-1
M3 - Article
C2 - 30242188
AN - SCOPUS:85053721436
SN - 2045-2322
VL - 8
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 14215
ER -