Calpain inhibition mediates autophagy-dependent protection against polyglutamine toxicity

• Published in: Cell death and differentiation Vol. 22; no. 3; pp. 433 - 444
• Main Authors: Menzies, F M, Garcia-Arencibia, M, Imarisio, S, O'Sullivan, N C, Ricketts, T, Kent, B A, Rao, M V, Lam, W, Green-Thompson, Z W, Nixon, R A, Saksida, L M, Bussey, T J, O'Kane, C J, Rubinsztein, D C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2015; Nature Publishing Group
• Subjects: 631/378/1689/1558; 631/80/82/39; 692/700/565/1436/2185; Animals; Apoptosis; Autophagy - drug effects; Biochemistry; Biomedical and Life Sciences; Calcium-Binding Proteins - biosynthesis; Calpain - antagonists & inhibitors; Calpain - genetics; Calpain - metabolism; Cell Biology; Cell Cycle Analysis; Disease Models, Animal; Drosophila; Drosophila Proteins - antagonists & inhibitors; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Female; Gene Knockdown Techniques; Huntington Disease - enzymology; Huntington Disease - metabolism; Huntington Disease - pathology; Huntington Disease - therapy; Inbreeding; Life Sciences; Male; Mice; Mice, Inbred C57BL; Original Paper; Peptides - metabolism; Signal Transduction; Stem Cells
• DOI: 10.1038/cdd.2014.151
• ISSN: 1350-9047

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.