The autophagy/lysosome pathway is impaired in SCA7 patients and SCA7 knock-in mice.

Sandro Alves, Florence Cormier-Dequaire, Martina Marinello, Thibaut Marais, Marie-Paule Muriel, Florian Beaumatin, Fanny Charbonnier-Beaupel, Khadija Tahiri, Danielle Seilhean, Khalid El Hachimi, Merle Ruberg, Giovanni Stevanin, Martine Barkats, Wilfred den Dunnen, Muriel Priault, Alexis Brice, Alexandra Durr, Jean-Christophe Corvol, Annie Sittler
Acta Neuropathol. 2014-05-24; 128(5): 705-722
DOI: 10.1007/s00401-014-1289-8

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1. Acta Neuropathol. 2014 Nov;128(5):705-22. doi: 10.1007/s00401-014-1289-8. Epub
2014 May 24.

The autophagy/lysosome pathway is impaired in SCA7 patients and SCA7 knock-in

Alves S(1), Cormier-Dequaire F, Marinello M, Marais T, Muriel MP, Beaumatin F,
Charbonnier-Beaupel F, Tahiri K, Seilhean D, El Hachimi K, Ruberg M, Stevanin G,
Barkats M, den Dunnen W, Priault M, Brice A, Durr A, Corvol JC, Sittler A.

Author information:
(1)Sorbonne Universités, UPMC Univ. Paris 6, ICM, 75013, Paris, France,

There is still no treatment for polyglutamine disorders, but clearance of mutant
proteins might represent a potential therapeutic strategy. Autophagy, the major
pathway for organelle and protein turnover, has been implicated in these
diseases. To determine whether the autophagy/lysosome system contributes to the
pathogenesis of spinocerebellar ataxia type 7 (SCA7), caused by expansion of a
polyglutamine tract in the ataxin-7 protein, we looked for biochemical,
histological and transcriptomic abnormalities in components of the
autophagy/lysosome pathway in a knock-in mouse model of the disease, postmortem
brain and peripheral blood mononuclear cells (PBMC) from patients. In the mouse
model, mutant ataxin-7 accumulated in inclusions immunoreactive for the
autophagy-associated proteins mTOR, beclin-1, p62 and ubiquitin. Atypical
accumulations of the autophagosome/lysosome markers LC3, LAMP-1, LAMP2 and
cathepsin-D were also found in the cerebellum of the SCA7 knock-in mice. In
patients, abnormal accumulations of autophagy markers were detected in the
cerebellum and cerebral cortex of patients, but not in the striatum that is
spared in SCA7, suggesting that autophagy might be impaired by the selective
accumulation of mutant ataxin-7. In vitro studies demonstrated that the
autophagic flux was impaired in cells overexpressing full-length mutant ataxin-7.
Interestingly, the expression of the early autophagy-associated gene ATG12 was
increased in PBMC from SCA7 patients in correlation with disease severity. These
results provide evidence that the autophagy/lysosome pathway is impaired in
neurons undergoing degeneration in SCA7. Autophagy/lysosome-associated molecules
might, therefore, be useful markers for monitoring the effects of potential
therapeutic approaches using modulators of autophagy in SCA7 and other
autophagy/lysosome-associated neurodegenerative disorders.

DOI: 10.1007/s00401-014-1289-8
PMID: 24859968 [Indexed for MEDLINE]

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