Abstract
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.
Highlights
Multiple-system atrophy (MSA) is a neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction
We established induced pluripotent stem cell (iPSC) from two patients (MSA_A and MSA_B) who were clinically diagnosed with cerebellar type of MSA
We examined the expression of COQ2 in iPSCs, using qRT-PCR, but MSA_A iPSCs did not show decreased expression level of COQ2
Summary
Multiple-system atrophy (MSA) is a neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. MSA-C has been reported to be more prevalent than MSA-P in the Japanese population, whereas MSA-P has been reported to be more prevalent than MSA-C in Europe and North America[8,9,10,11] These reports indicate that genetic factors confer susceptibility to the disease. We observed that functionally impaired heterozygous COQ2 variants were associated with sporadic MSA. The activity of COQ2 in lymphoblastoid cell lines with the COQ2 variant p.V393A, established from patients with MSA, was significantly lower than that in control cell lines, and the level of coenzyme Q10 activity in frozen cerebellum samples obtained from a patient carrying a homozygous mutation was substantially lower than the levels observed in controls without the mutation[12]. Our findings suggest that impaired COQ2 activity, which is predicted to impair the mitochondrial respiratory chain and increase vulnerability to oxidative stress, confers susceptibility to MSA
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