Metabolic and Organelle Morphology Defects in Mice and Human Patients Define Spinocerebellar Ataxia Type 7 as a Mitochondrial Disease
Jacqueline M. Ward,
Colleen A. Stoyas,
Pawel M. Switonski,
Farid Ichou,
Weiwei Fan,
Brett Collins,
Christopher E. Wall,
Isaac Adanyeguh,
Chenchen Niu,
Bryce L. Sopher,
Chizuru Kinoshita,
Richard S. Morrison,
Alexandra Durr,
Alysson R. Muotri,
Ronald M. Evans,
Fanny Mochel,
Albert R. La Spada
Affiliations
Jacqueline M. Ward
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
Colleen A. Stoyas
Department of Neurology, Duke University School of Medicine, Durham, NC 27710, USA
Pawel M. Switonski
Department of Neurology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Molecular Biomedicine, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14 Str., 61-704 Poznan, Poland
Farid Ichou
Metabolomics Core Facility, Institute of Cardiometabolism and Nutrition, ICAN, Paris, France
Weiwei Fan
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
Brett Collins
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
Christopher E. Wall
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
Isaac Adanyeguh
ICM, Sorbonne Université, UPMC-Paris 6, UMR S 1127 / INSERM U 1127 / CNRS UMR 7225 / ICM, 75013, Paris, France
Chenchen Niu
Department of Neurology, Duke University School of Medicine, Durham, NC 27710, USA
Bryce L. Sopher
Department of Neurology, University of Washington, Seattle, WA 98195, USA
Chizuru Kinoshita
Department of Neurosurgery, University of Washington, Seattle, WA 98195, USA
Richard S. Morrison
Department of Neurosurgery, University of Washington, Seattle, WA 98195, USA
Alexandra Durr
ICM, Sorbonne Université, UPMC-Paris 6, UMR S 1127 / INSERM U 1127 / CNRS UMR 7225 / ICM, 75013, Paris, France; Department of Genetics, APHP, La Pitie-Salpêtriere University Hospital, Paris, France
Alysson R. Muotri
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Department Cellular & Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA
Ronald M. Evans
Metabolomics Core Facility, Institute of Cardiometabolism and Nutrition, ICAN, Paris, France; Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
Fanny Mochel
ICM, Sorbonne Université, UPMC-Paris 6, UMR S 1127 / INSERM U 1127 / CNRS UMR 7225 / ICM, 75013, Paris, France; Department of Genetics, APHP, La Pitie-Salpêtriere University Hospital, Paris, France
Albert R. La Spada
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Department Cellular & Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA; Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Department of Neurobiology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA; Duke Center for Neurodegeneration & Neurotherapeutics, Duke University School of Medicine, Durham, NC 27710, USA; Corresponding author
Summary: Spinocerebellar ataxia type 7 (SCA7) is a retinal-cerebellar degenerative disorder caused by CAG-polyglutamine (polyQ) repeat expansions in the ataxin-7 gene. As many SCA7 clinical phenotypes occur in mitochondrial disorders, and magnetic resonance spectroscopy of patients revealed altered energy metabolism, we considered a role for mitochondrial dysfunction. Studies of SCA7 mice uncovered marked impairments in oxygen consumption and respiratory exchange. When we examined cerebellar Purkinje cells in mice, we observed mitochondrial network abnormalities, with enlarged mitochondria upon ultrastructural analysis. We developed stem cell models from patients and created stem cell knockout rescue systems, documenting mitochondrial morphology defects, impaired oxidative metabolism, and reduced expression of nicotinamide adenine dinucleotide (NAD+) production enzymes in SCA7 models. We observed NAD+ reductions in mitochondria of SCA7 patient NPCs using ratiometric fluorescent sensors and documented alterations in tryptophan-kynurenine metabolism in patients. Our results indicate that mitochondrial dysfunction, stemming from decreased NAD+, is a defining feature of SCA7. : Ward et al. document altered metabolism and mitochondrial dysfunction in SCA7 patients, mice, and human stem cell-derived neurons. They link these abnormalities to reduced nicotinamide adenine dinucleotide in specific subcellular compartments. Given the role of mitochondrial impairment in neurodegeneration, their results have therapeutic implications for SCA7 and related neurological disorders. Keywords: spinocerebellar ataxia, polyglutamine, trinucleotide repeat, mitochondria, oxidative metabolism, nicotinamide adenine dinucleotide, Purkinje cell, ataxin-7, mouse model, induced pluripotent stem cells
