Constitutive upregulation of chaperone-mediated autophagy in Huntington's disease

Hiroshi Koga, Marta Martinez-Vicente, Esperanza Arias-Perez, Susmita Kaushik, David Sulzer, Ana Maria Cuervo

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

Autophagy contributes to the removal of prone-to-aggregate proteins, but in several instances these pathogenic proteins have been shown to interfere with autophagic activity. In the case of Huntington's disease (HD), a congenital neurodegenerative disorder resulting from mutation in the hunting tin protein, we have previously described that the mutant protein interferes with the ability of autophagic vacuoles to recognize cytosolic cargo. Growing evidence supports the existence of cross talk among autophagic pathways, suggesting the possibility of functional compensation when one of them is compromised. In this study, we have identified a compensatory upregulation of chaperone-mediated autophagy (CMA) in different cellular and mouse models of HD. Components of CMA, namely the lysosome associated membrane protein type 2A (LAMP-2A) and lysosomal-hsc70, are markedly increased in HD models. The increase in LAMP-2A is achieved through both an increase in the stability of this protein at the lysosomal membrane and transcriptional upregulation of this splice variant of the lamp-2 gene. We propose that CMA activity increases in response to macroautophagic dysfunction in the early stages of HD, but that the efficiency of this compensatory mechanism may decrease with age and so contribute to cellular failure and the onset of pathological manifestations.

Original languageEnglish (US)
Pages (from-to)18492-18505
Number of pages14
JournalJournal of Neuroscience
Volume31
Issue number50
DOIs
StatePublished - Dec 14 2011

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Huntington Disease
Autophagy
Lysosome-Associated Membrane Glycoproteins
Up-Regulation
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Aptitude
Tin
Mutant Proteins
Vacuoles
Neurodegenerative Diseases
Proteins
Efficiency
Mutation
Genes

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Constitutive upregulation of chaperone-mediated autophagy in Huntington's disease. / Koga, Hiroshi; Martinez-Vicente, Marta; Arias-Perez, Esperanza; Kaushik, Susmita; Sulzer, David; Cuervo, Ana Maria.

In: Journal of Neuroscience, Vol. 31, No. 50, 14.12.2011, p. 18492-18505.

Research output: Contribution to journalArticle

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AU - Cuervo, Ana Maria

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