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Neuronal mitochondrial dysfunction in sporadic amyotrophic lateral sclerosis is developmentally regulated.

ABSTRACT: Amyotrophic lateral sclerosis is an adult-onset neurodegenerative disorder characterized by loss of motor neurons. Mitochondria are essential for neuronal survival but the developmental timing and mechanistic importance of mitochondrial dysfunction in sporadic ALS (sALS) neurons is not fully understood. We used human induced pluripotent stem cells and generated a developmental timeline by differentiating sALS iPSCs to neural progenitors and to motor neurons and comparing mitochondrial parameters with familial ALS (fALS) and control cells at each developmental stage. We report that sALS and fALS motor neurons have elevated reactive oxygen species levels, depolarized mitochondria, impaired oxidative phosphorylation, ATP loss and defective mitochondrial protein import compared with control motor neurons. This phenotype develops with differentiation into motor neurons, the affected cell type in ALS, and does not occur in the parental undifferentiated sALS cells or sALS neural progenitors. Our work demonstrates a developmentally regulated unifying mitochondrial phenotype between patient derived sALS and fALS motor neurons. The occurrence of a unifying mitochondrial phenotype suggests that mitochondrial etiology known to SOD1-fALS may applicable to sALS. Furthermore, our findings suggest that disease-modifying treatments focused on rescue of mitochondrial function may benefit both sALS and fALS patients.

SUBMITTER: Singh T

PROVIDER: S-EPMC8460779 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundMitochondrial dysregulation and aberrant epigenetic mechanisms have been frequently reported in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), and several researchers suggested that epigenetic dysregulation in mitochondrial DNA (mtDNA) could contribute to the neurodegenerative process. We recently screened families with mutations in the major ALS causative genes, namely C9orf72, SOD1, FUS, and TARDBP, observing reduced methylation levels of the mtDNA regulatory region (D-loop) only in peripheral lymphocytes of SOD1 carriers. However, until now no studies investigated the potential role of mtDNA methylation impairment in the sporadic form of ALS, which accounts for the majority of disease cases. The aim of the current study was to investigate the D-loop methylation levels and the mtDNA copy number in sporadic ALS patients and compare them to those observed in healthy controls and in familial ALS patients. Pyrosequencing analysis of D-loop methylation levels and quantitative analysis of mtDNA copy number were performed in peripheral white blood cells from 36 sporadic ALS patients, 51 age- and sex-matched controls, and 27 familial ALS patients with germinal mutations in SOD1 or C9orf72 that represent the major familial ALS forms.ResultsIn the total sample, D-loop methylation levels were significantly lower in ALS patients compared to controls, and a significant inverse correlation between D-loop methylation levels and the mtDNA copy number was observed. Stratification of ALS patients into different subtypes revealed that both SOD1-mutant and sporadic ALS patients showed lower D-loop methylation levels compared to controls, while C9orf72-ALS patients showed similar D-loop methylation levels than controls. In healthy controls, but not in ALS patients, D-loop methylation levels decreased with increasing age at sampling and were higher in males compared to females.ConclusionsPresent data reveal altered D-loop methylation levels in sporadic ALS and confirm previous evidence of an inverse correlation between D-loop methylation levels and the mtDNA copy number, as well as differences among the major familial ALS subtypes. Overall, present results suggest that D-loop methylation and mitochondrial replication are strictly related to each other and could represent compensatory mechanisms to counteract mitochondrial impairment in sporadic and SOD1-related ALS forms.

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Neuronal mitochondrial dysfunction in sporadic amyotrophic lateral sclerosis is developmentally regulated.

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