title: Calpain inhibition mediates autophagy-dependent protection against polyglutamine toxicity.
abstract: Over recent years, accumulated evidence suggests that autophagy induction is protective in animal models of a number of neurodegenerative diseases. Intense research in the field has elucidated different pathways through which autophagy can be upregulated and it is important to establish how modulation of these pathways impacts upon disease progression in vivo and therefore which, if any, may have further therapeutic relevance. In addition, it is important to understand how alterations in these target pathways may affect normal physiology when constitutively modulated over a long time period, as would be required for treatment of neurodegenerative diseases. Here we evaluate the potential protective effect of downregulation of calpains. We demonstrate, in Drosophila, that calpain knockdown protects against the aggregation and toxicity of proteins, like mutant huntingtin, in an autophagy-dependent fashion. Furthermore, we demonstrate that, overexpression of the calpain inhibitor, calpastatin, increases autophagosome levels and is protective in a mouse model of Huntington's disease, improving motor signs and delaying the onset of tremors. Importantly, long-term inhibition of calpains did not result in any overt deleterious phenotypes in mice. Thus, calpain inhibition, or activation of autophagy pathways downstream of calpains, may be suitable therapeutic targets for diseases like Huntington's disease.
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: F M
authors.initials: FM
authors.lastname: Menzies
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: M
authors.initials: M
authors.lastname: Garcia-Arencibia
authors.affiliation: Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
authors.forename: S
authors.initials: S
authors.lastname: Imarisio
authors.affiliation: Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
authors.forename: N C
authors.initials: NC
authors.lastname: O'Sullivan
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: T
authors.initials: T
authors.lastname: Ricketts
authors.affiliation: 1] Department of Psychology, University of Cambridge, Cambridge, UK [2] Translational and Cognitive Neuroscience Laboratory, MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.
authors.forename: B A
authors.initials: BA
authors.lastname: Kent
authors.affiliation: 1] Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY, USA [2] Department of Psychiatry, New York University Langone Medical Center, New York, NY, USA [3] Department of Cell Biology, New York University Langone Medical Center, New York, NY, USA.
authors.forename: M V
authors.initials: MV
authors.lastname: Rao
authors.affiliation: Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
authors.forename: W
authors.initials: W
authors.lastname: Lam
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Z W
authors.initials: ZW
authors.lastname: Green-Thompson
authors.affiliation: 1] Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY, USA [2] Department of Psychiatry, New York University Langone Medical Center, New York, NY, USA [3] Department of Cell Biology, New York University Langone Medical Center, New York, NY, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Nixon
authors.affiliation: 1] Department of Psychology, University of Cambridge, Cambridge, UK [2] Translational and Cognitive Neuroscience Laboratory, MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.
authors.forename: L M
authors.initials: LM
authors.lastname: Saksida
authors.affiliation: 1] Department of Psychology, University of Cambridge, Cambridge, UK [2] Translational and Cognitive Neuroscience Laboratory, MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.
authors.forename: T J
authors.initials: TJ
authors.lastname: Bussey
authors.affiliation: Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: O'Kane
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: D C
authors.initials: DC
authors.lastname: Rubinsztein
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002135:Calcium-Binding Proteins / Q000096:biosynthesis; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006816:Huntington Disease / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D007178:Inbreeding; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D002135:Calcium-Binding Proteins; D029721:Drosophila Proteins; D010455:Peptides; C097188:polyglutamine; C033668:calpastatin; D002154:Calpain; C569839:calpain A, Drosophila