title: Mitochondrial impairments contribute to Spinocerebellar ataxia type 1 progression and can be ameliorated by the mitochondria-targeted antioxidant MitoQ.
abstract: Spinocerebellar ataxia type 1 (SCA1), due to an unstable polyglutamine expansion within the ubiquitously expressed Ataxin-1 protein, leads to the premature degeneration of Purkinje cells (PCs), decreasing motor coordination and causing death within 10-15 years of diagnosis. Currently, there are no therapies available to slow down disease progression. As secondary cellular impairments contributing to SCA1 progression are poorly understood, here, we focused on identifying those processes by performing a PC specific proteome profiling of Sca1(154Q/2Q) mice at a symptomatic stage. Mass spectrometry analysis revealed prominent alterations in mitochondrial proteins. Immunohistochemical and serial block-face scanning electron microscopy analyses confirmed that PCs underwent age-dependent alterations in mitochondrial morphology. Moreover, colorimetric assays demonstrated impairment of the electron transport chain complexes (ETC) and decrease in ATPase activity. Subsequently, we examined whether the mitochondria-targeted antioxidant MitoQ could restore mitochondrial dysfunction and prevent SCA1-associated pathology in Sca1(154Q/2Q) mice. MitoQ treatment both presymptomatically and when symptoms were evident ameliorated mitochondrial morphology and restored the activities of the ETC complexes. Notably, MitoQ slowed down the appearance of SCA1-linked neuropathology such as lack of motor coordination as well as prevented oxidative stress-induced DNA damage and PC loss. Our work identifies a central role for mitochondria in PC degeneration in SCA1 and provides evidence for the supportive use of mitochondria-targeted therapeutics in slowing down disease progression.
authors.affiliation: Institute of Cell Biology, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: David M
authors.initials: DM
authors.lastname: Stucki
authors.affiliation: Institute of Cell Biology, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: Céline
authors.initials: C
authors.lastname: Ruegsegger
authors.affiliation: Institute of Cell Biology, University of Bern, Bern, Switzerland.
authors.forename: Silvio
authors.initials: S
authors.lastname: Steiner
authors.affiliation: Institute of Anatomy, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: Julika
authors.initials: J
authors.lastname: Radecke
authors.affiliation: Medical Research Council, Mitochondrial Biology Unit, Cambridge, United Kingdom.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: Institute of Anatomy, University of Bern, Bern, Switzerland.
authors.forename: Benoît
authors.initials: B
authors.lastname: Zuber
authors.affiliation: Institute of Cell Biology, University of Bern, Bern, Switzerland. Electronic address: smita.saxena@izb.unibe.ch.
authors.forename: Smita
authors.initials: S
authors.lastname: Saxena
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000235:genetics; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009943:Organophosphorus Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress; D020543:Proteome / Q000378:metabolism; D020754:Spinocerebellar Ataxias / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000975:Antioxidants; D004272:DNA, Mitochondrial; D009943:Organophosphorus Compounds; D020543:Proteome; D014451:Ubiquinone; C429014:mitoquinone
keywords: Antioxidant MitoQ; Electron transport chain (ETC) activities; Mitochondria; Neurodegeneration; Oxidative stress; Purkinje cells; Spinocerebellar ataxia type 1