Publications

Latest publication 03/01/2015

Calpain inhibition mediates autophagy-dependent protection against polyglutamine

Over recent years, accumulated evidence suggests that autophagy induction is protective in animal models of a number of neurodegenerative diseases....

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    [title] => Calpain inhibition mediates autophagy-dependent protection against polyglutamine
    [paragraph] => Calpain inhibition mediates autophagy-dependent protection against polyglutamine toxicity.
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Authors
Menzies FM, Garcia-Arencibia M, Imarisio S, o'sullivan NC, Ricketts T, Kent BA, Rao MV, Lam W, Green-Thompson ZW, Nixon RA, Saksida LM, Bussey TJ, o'kane CJ, Rubinsztein DC

 Lab
Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge, UK
Journal
Cell Death Differ.
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.
BIOSEB Instruments Used
Grip strength test (BIO-GS3)
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An easy way to objectively quantify the muscular strength of mice and rats, and to assess the effect of drugs, toxins, muscular (i.e. myopathy) and neurodegenerative diseases on muscular degeneration. It is widely used in conjunction with the ROTAROD motor coordination test: a normally coordinated rodent will show a decreased latency to fall off the rotating rod if its muscular strength is low. The Grip Strength Test is a must for your research on activity, motor control & coordination, and is particularly well suited for studies on Parkinson's & Huntington's disease.
New features GS4 - 2023: Color display with permanent backlight screen for easier reading, reset by footswitch, Improved battery time, Larger data memory of 500 values, Animal counter, USB port (charging/data transfer)

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