Short-term succinic acid treatment mitigates cerebellar mitochondrial OXPHOS dysfunction, neurodegeneration and ataxia in a Purkinje-specific spinocerebellar ataxia type 1 (SCA1) mouse model

Austin Ferro, Emily Carbone, Jenny Zhang, Evan Marzouk, Monica Villegas, Asher Siegel, Donna Nguyen, Thomas Possidente, Jessilyn Hartman, Kailen Polley, Melissa A Ingram, Georgia Berry, Thomas H Reynolds, Bernard Possidente, Kimberley Frederick, Stephen Ives, Sarita Lagalwar

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Mitochondrial dysfunction plays a significant role in neurodegenerative disease including ataxias and other movement disorders, particularly those marked by progressive degeneration in the cerebellum. In this study, we investigate the role of mitochondrial oxidative phosphorylation (OXPHOS) deficits in cerebellar tissue of a Purkinje cell-driven spinocerebellar ataxia type 1 (SCA1) mouse. Using RNA sequencing transcriptomics, OXPHOS complex assembly analysis and oxygen consumption assays, we report that in the presence of mutant polyglutamine-expanded ataxin-1, SCA1 mice display deficits in cerebellar OXPHOS complex I (NADH-coenzyme Q oxidoreductase). Complex I genes are upregulated at the time of symptom onset and upregulation persists into late stage disease; yet, functional assembly of complex I macromolecules are diminished and oxygen respiration through complex I is reduced. Acute treatment of postsymptomatic SCA1 mice with succinic acid, a complex II (succinate dehydrogenase) electron donor to bypass complex I dysfunction, ameliorated cerebellar OXPHOS dysfunction, reduced cerebellar pathology and improved motor behavior. Thus, exploration of mitochondrial dysfunction and its role in neurodegenerative ataxias, and warrants further investigation.

Original languageEnglish (US)
Pages (from-to)e0188425
JournalPloS one
Volume12
Issue number12
DOIs
StatePublished - 2017
Externally publishedYes

Keywords

  • Animals
  • Cerebellum/metabolism
  • Disease Models, Animal
  • Mice
  • Mice, Transgenic
  • Mitochondria/metabolism
  • Oxidative Phosphorylation
  • Purkinje Cells/pathology
  • Spinocerebellar Ataxias/metabolism
  • Succinic Acid/administration & dosage

PubMed: MeSH publication types

  • Journal Article

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    Ferro, A., Carbone, E., Zhang, J., Marzouk, E., Villegas, M., Siegel, A., Nguyen, D., Possidente, T., Hartman, J., Polley, K., Ingram, M. A., Berry, G., Reynolds, T. H., Possidente, B., Frederick, K., Ives, S., & Lagalwar, S. (2017). Short-term succinic acid treatment mitigates cerebellar mitochondrial OXPHOS dysfunction, neurodegeneration and ataxia in a Purkinje-specific spinocerebellar ataxia type 1 (SCA1) mouse model. PloS one, 12(12), e0188425. https://doi.org/10.1371/journal.pone.0188425