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Metabolic and Organelle Morphology Defects in Mice and Human Patients Define Spinocerebellar Ataxia Type 7 as a Mitochondrial Disease.

Publication ,  Journal Article
Ward, JM; Stoyas, CA; Switonski, PM; Ichou, F; Fan, W; Collins, B; Wall, CE; Adanyeguh, I; Niu, C; Sopher, BL; Kinoshita, C; Morrison, RS ...
Published in: Cell Rep
January 29, 2019

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.

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Published In

Cell Rep

DOI

EISSN

2211-1247

Publication Date

January 29, 2019

Volume

26

Issue

5

Start / End Page

1189 / 1202.e6

Location

United States

Related Subject Headings

  • Tryptophan
  • Trinucleotide Repeat Expansion
  • Spinocerebellar Ataxias
  • Reproducibility of Results
  • Purkinje Cells
  • Phenotype
  • Peptides
  • Organelles
  • Neural Stem Cells
  • NAD
 

Citation

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Ward, J. M., Stoyas, C. A., Switonski, P. M., Ichou, F., Fan, W., Collins, B., … La Spada, A. R. (2019). Metabolic and Organelle Morphology Defects in Mice and Human Patients Define Spinocerebellar Ataxia Type 7 as a Mitochondrial Disease. Cell Rep, 26(5), 1189-1202.e6. https://doi.org/10.1016/j.celrep.2019.01.028
Ward, Jacqueline M., Colleen A. Stoyas, Pawel M. Switonski, Farid Ichou, Weiwei Fan, Brett Collins, Christopher E. Wall, et al. “Metabolic and Organelle Morphology Defects in Mice and Human Patients Define Spinocerebellar Ataxia Type 7 as a Mitochondrial Disease.Cell Rep 26, no. 5 (January 29, 2019): 1189-1202.e6. https://doi.org/10.1016/j.celrep.2019.01.028.
Ward JM, Stoyas CA, Switonski PM, Ichou F, Fan W, Collins B, et al. Metabolic and Organelle Morphology Defects in Mice and Human Patients Define Spinocerebellar Ataxia Type 7 as a Mitochondrial Disease. Cell Rep. 2019 Jan 29;26(5):1189-1202.e6.
Ward, Jacqueline M., et al. “Metabolic and Organelle Morphology Defects in Mice and Human Patients Define Spinocerebellar Ataxia Type 7 as a Mitochondrial Disease.Cell Rep, vol. 26, no. 5, Jan. 2019, pp. 1189-1202.e6. Pubmed, doi:10.1016/j.celrep.2019.01.028.
Ward JM, Stoyas CA, Switonski PM, Ichou F, Fan W, Collins B, Wall CE, Adanyeguh I, Niu C, Sopher BL, Kinoshita C, Morrison RS, Durr A, Muotri AR, Evans RM, Mochel F, La Spada AR. Metabolic and Organelle Morphology Defects in Mice and Human Patients Define Spinocerebellar Ataxia Type 7 as a Mitochondrial Disease. Cell Rep. 2019 Jan 29;26(5):1189-1202.e6.
Journal cover image

Published In

Cell Rep

DOI

EISSN

2211-1247

Publication Date

January 29, 2019

Volume

26

Issue

5

Start / End Page

1189 / 1202.e6

Location

United States

Related Subject Headings

  • Tryptophan
  • Trinucleotide Repeat Expansion
  • Spinocerebellar Ataxias
  • Reproducibility of Results
  • Purkinje Cells
  • Phenotype
  • Peptides
  • Organelles
  • Neural Stem Cells
  • NAD