Can 'calpain-cathepsin hypothesis' explain Alzheimer neuronal death?

Can 'calpain-cathepsin hypothesis' explain Alzheimer neuronal death?
Ageing Res Rev. 2016 Jun 12;
Authors: Yamashima T
Abstract
Neurons are highly specialized post-mitotic cells, so their homeostasis and survival depend on the tightly-regulated, continuous protein degradation, synthesis, and turnover. In neurons, autophagy is indispensable to facilitate recycling of long-lived, damaged proteins and organelles in a lysosome-dependent manner. Since lysosomal proteolysis under basal conditions performs an essential housekeeping function, inhibition of the proteolysis exacerbates level of neurodegeneration. The latter is characterized by an accumulation of abnormal proteins or organelles within autophagic vacuoles which reveal as 'granulo-vacuolar degenerations' on microscopy. Heat-shock protein70.1 (Hsp70.1), as a means of molecular chaperone and lysosomal stabilizer, is a potent survival protein that confers neuroprotection against diverse stimuli, but its depletion induces neurodegeneration via autophagy failure. In response to hydroxynonenal generated from linoleic or arachidonic acids by the reactive oxygen species, a specific oxidative injury 'carbonylation' occurs at the key site Arg469 of Hsp70.1. Oxidative stress-induced carbonylation of Hsp70.1, in coordination with the calpain-mediated cleavage, leads to lysosomal destabilization/rupture and release of cathepsins with the resultant neuronal death. Hsp70.1 carbonylation which o...

Source: Ageing Research Reviews - June 11, 2016 Category: Genetics & Stem Cells Authors: Yamashima T Tags: Ageing Res Rev Source Type: research