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CCP1 promotes mitochondrial fusion and motility to prevent Purkinje cell neuron loss in pcd mice.

Publication ,  Journal Article
Gilmore-Hall, S; Kuo, J; Ward, JM; Zahra, R; Morrison, RS; Perkins, G; La Spada, AR
Published in: J Cell Biol
January 7, 2019

A perplexing question in neurodegeneration is why different neurons degenerate. The Purkinje cell degeneration (pcd) mouse displays a dramatic phenotype of degeneration of cerebellar Purkinje cells. Loss of CCP1/Nna1 deglutamylation of tubulin accounts for pcd neurodegeneration, but the mechanism is unknown. In this study, we modulated the dosage of fission and fusion genes in a Drosophila melanogaster loss-of-function model and found that mitochondrial fragmentation and disease phenotypes were rescued by reduced Drp1. We observed mitochondrial fragmentation in CCP1 null cells and in neurons from pcd mice, and we documented reduced mitochondrial fusion in cells lacking CCP1. We examined the effect of tubulin hyperglutamylation on microtubule-mediated mitochondrial motility in pcd neurons and noted markedly reduced retrograde axonal transport. Mitochondrial stress promoted Parkin-dependent turnover of CCP1, and CCP1 and Parkin physically interacted. Our results indicate that CCP1 regulates mitochondrial motility through deglutamylation of tubulin and that loss of CCP1-mediated mitochondrial fusion accounts for the exquisite vulnerability of Purkinje neurons in pcd mice.

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Published In

J Cell Biol

DOI

EISSN

1540-8140

Publication Date

January 7, 2019

Volume

218

Issue

1

Start / End Page

206 / 219

Location

United States

Related Subject Headings

  • Ubiquitin-Protein Ligases
  • Tubulin
  • Signal Transduction
  • Purkinje Cells
  • Phenotype
  • Neurodegenerative Diseases
  • Nerve Tissue Proteins
  • Mitochondrial Dynamics
  • Mitochondria
  • Mice, Knockout
 

Citation

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Gilmore-Hall, S., Kuo, J., Ward, J. M., Zahra, R., Morrison, R. S., Perkins, G., & La Spada, A. R. (2019). CCP1 promotes mitochondrial fusion and motility to prevent Purkinje cell neuron loss in pcd mice. J Cell Biol, 218(1), 206–219. https://doi.org/10.1083/jcb.201709028
Gilmore-Hall, Stephen, Jennifer Kuo, Jacqueline M. Ward, Rabaab Zahra, Richard S. Morrison, Guy Perkins, and Albert R. La Spada. “CCP1 promotes mitochondrial fusion and motility to prevent Purkinje cell neuron loss in pcd mice.J Cell Biol 218, no. 1 (January 7, 2019): 206–19. https://doi.org/10.1083/jcb.201709028.
Gilmore-Hall S, Kuo J, Ward JM, Zahra R, Morrison RS, Perkins G, et al. CCP1 promotes mitochondrial fusion and motility to prevent Purkinje cell neuron loss in pcd mice. J Cell Biol. 2019 Jan 7;218(1):206–19.
Gilmore-Hall, Stephen, et al. “CCP1 promotes mitochondrial fusion and motility to prevent Purkinje cell neuron loss in pcd mice.J Cell Biol, vol. 218, no. 1, Jan. 2019, pp. 206–19. Pubmed, doi:10.1083/jcb.201709028.
Gilmore-Hall S, Kuo J, Ward JM, Zahra R, Morrison RS, Perkins G, La Spada AR. CCP1 promotes mitochondrial fusion and motility to prevent Purkinje cell neuron loss in pcd mice. J Cell Biol. 2019 Jan 7;218(1):206–219.

Published In

J Cell Biol

DOI

EISSN

1540-8140

Publication Date

January 7, 2019

Volume

218

Issue

1

Start / End Page

206 / 219

Location

United States

Related Subject Headings

  • Ubiquitin-Protein Ligases
  • Tubulin
  • Signal Transduction
  • Purkinje Cells
  • Phenotype
  • Neurodegenerative Diseases
  • Nerve Tissue Proteins
  • Mitochondrial Dynamics
  • Mitochondria
  • Mice, Knockout