Cited by 112Autophagy in Disease and TherapyGenetic Neurodegenerative DiseasesCell death mechanisms and regulation

Autophagy activation and enhanced mitophagy characterize the Purkinje cells of pcd mice prior to neuronal death

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Chakrabarti, Lisa, Eng, Jeremiah, Ivanov, Nishi, Garden, Gwenn A, La Spada, Albert R·2009·Molecular Brain

Abstract

Purkinje cells are a class of specialized neurons in the cerebellum, and are among the most metabolically active of all neurons, as they receive immense synaptic stimulation, and provide the only efferent output from the cerebellum. Degeneration of Purkinje cells is a common feature of inherited ataxias in humans and mice. To understand Purkinje neuron degeneration, investigators have turned to naturally occurring Purkinje cell degeneration phenotypes in mice to identify key regulatory proteins and cellular pathways. The Purkinje cell degeneration (pcd) mouse is a recessive mutant characterized by complete and dramatic post-natal, cell autonomous Purkinje neuron degeneration and death. As the basis of Purkinje cell death in pcd is unresolved, and contradictory data has emerged for the role of autophagy in Purkinje cell degeneration, we studied the mechanism of Purkinje cell death in pcd mice. BAX null status did not suppress Purkinje neuron death in pcd mice, indicating that classic apoptosis is not responsible for Purkinje cell loss. Interestingly, LC3 Western blot analysis and GFP-LC3 immunostaining of degenerating pcd cerebellum revealed activation of the autophagy pathway. Ultrastructural studies confirmed increased autophagy pathway activity in Purkinje cells, and yielded evidence for mitophagy, in agreement with LC3 immunoblotting of cerebellar fractions. As p62 levels were decreased in pcd cerebellum, our findings suggest that pcd Purkinje cell neurons can execute effective autophagy. However, our results support a role for dysregulated autophagy activation in pcd, and suggest that increased or aberrant mitophagy contributes to the Purkinje cell degeneration in pcd mice.

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  • Purkinje cell degeneration models such as pcd mice display motor abnormalities that were similar to those observed in B6.Clec16aGT/GT and Clec16aCURT/CURT mice.

    “Purkinje cell degeneration models such as pcd mice display motor abnormalities that were similar to those observed in B6.Clec16aGT/GT and Clec16aCURT/CURT mice3031 and staining with the Purkinje cell marker calbindin confirmed loss of these cells in B6.Clec16aGT/GT mice (Fig. 2d) at 8 weeks of age that was dramatically increased by 47 weeks of age (Supplementary Fig. 2e).”

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Authors
Chakrabarti, L., Eng, J., Ivanov, N., Garden, G. A., & La Spada, A. R.
Affiliations
University of Washington (US)
Venue
Molecular Brain
Published
2009-07-29
Volume
2
Issue
1
Pages
24-24
ISSN
1756-6606 (ISSN-L)
OpenAlex
W2028695079
Cited by
112
References
36
Citations by year
2026: 2 · 2025: 4 · 2024: 7 · 2023: 5 · 2022: 1 · 2021: 4 · 2020: 8 · 2019: 5 · 2018: 7 · 2017: 1 · 2016: 15 · 2015: 5 · 2014: 13 · 2013: 13 · 2012: 10
FWCI
4.95
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Molecular Brain (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (EY-01730, HD02274)
  • Intellectual and Developmental Disabilities Research Center
  • National Eye Institute (EY 18106, EY-01730, R01EY014997, R21EY018106, P30EY001730, EY 14997)
  • National Institute of Neurological Disorders and Stroke (R01NS052535)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD02274, P30HD002274)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
Purkinje cells, Purkinje cell degeneration, autophagy, mitophagy, neuronal cell death, Bax, apoptosis, LC3, p62, cerebellum, hereditary ataxia, neurodegeneration
MeSH terms
Animals, Ataxia, Autophagy, Dendrites, Endoplasmic Reticulum, Mice, Neurologic Mutants, Mitochondria, Nerve Degeneration, Phagosomes, Phenotype, Purkinje Cells, bcl-2-Associated X Protein, Mice

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