Williams A, Sarkar S, Cuddon P, Ttofi EK, Saiki S, Siddiqi FH, Jahreiss L, Fleming A, Pask D, Goldsmith P, O'Kane CJ, Floto RA, Rubinsztein DC. Novel targets for Huntington's disease in an mTOR-independent autophagy pathway. Nat Chem Biol. 2008 May;4(5):295-305. PubMed.
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New York University School of Medicine/Nathan Kline Institute
The findings reported by the Rubinsztein group on new targets for Huntington disease also have potential implications for the pathogenesis and treatment of Alzheimer disease. In both diseases, less-than-effective autophagy contributes to intracellular protein accumulations, and calpain overactivation contributes to neurodegeneration. In Alzheimer disease, the trail of neuropathology left by overactivated calpains is amply evident in the activation of multiple protein kinases, tau hyperphosphorylation, and altered phosphorylation and breakdown of structural proteins, including proteins that have been implicated in synaptic plasticity, learning, and memory. Markedly defective autophagy in the AD brain is evidenced by a massive build-up of autophagic vacuoles in dystrophic neurites. These accumulated vacuoles are also a major reservoir of intracellular Aβ that is generated when APP is turned over by autophagy but is not effectively cleared by lysosomes. The exciting new data from Williams and colleagues potentially link these putative pathogenic mechanisms in AD.
Given that calpains are proposed to act at the level of autophagosome synthesis, calpain overactivation is unlikely to explain fully the autophagy deficit in AD brain, which our data suggest also involves defective autophagosome clearance. Overactivation of these proteases may, nevertheless, represent an additional route by which autophagy function may be disrupted in compromised neurons in AD. Importantly, the ability of calpain inhibitors to stimulate autophagy provides one more rationale for considering them as promising agents in the treatment of neurodegenerative diseases, including Alzheimer’s and Huntington’s. The challenge, as it has been for many years, is to develop selective inhibitors of calpains that will not block other cysteine proteases mediating various neuronal functions, including lysosomal degradation.
References:
Nixon RA. The calpains in aging and aging-related diseases. Ageing Res Rev. 2003 Oct;2(4):407-18. PubMed.
Nixon RA. Autophagy, amyloidogenesis and Alzheimer disease. J Cell Sci. 2007 Dec 1;120(Pt 23):4081-91. PubMed.
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