title: Constitutive upregulation of chaperone-mediated autophagy in Huntington's disease.
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 huntingtin 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.
authors.affiliation: Department of Developmental and Molecular Biology and Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Koga
authors.forename: Marta
authors.initials: M
authors.lastname: Martinez-Vicente
authors.forename: Esperanza
authors.initials: E
authors.lastname: Arias
authors.forename: Susmita
authors.initials: S
authors.lastname: Kaushik
authors.forename: David
authors.initials: D
authors.lastname: Sulzer
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Cuervo
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D004195:Disease Models, Animal; D050883:HSC70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D052119:Lysosomal-Associated Membrane Protein 2 / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D050883:HSC70 Heat-Shock Proteins; D052119:Lysosomal-Associated Membrane Protein 2; D018832:Molecular Chaperones