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Can 'calpain-cathepsin hypothesis' explain Alzheimer neuronal death?
- Source :
- Ageing research reviews. 32
- Publication Year :
- 2015
-
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 occurs anywhere in the brain is indispensable for neuronal death, but extent of calpain activation should be more crucial for determining the cell death fate. Importantly, not only acute ischemia during stroke but also chronic ischemia due to ageing may cause calpain activation. Here, role of Hsp70.1-mediated lysosomal rupture is discussed by comparing ischemic and Alzheimer neuronal death. A common neuronal death cascade may exist between cerebral ischemia and Alzheimer's disease.
- Subjects :
- 0301 basic medicine
Programmed cell death
Aging
Proteolysis
Biology
Protein degradation
Biochemistry
Neuroprotection
Brain Ischemia
03 medical and health sciences
Alzheimer Disease
medicine
Animals
Humans
Molecular Biology
Cathepsin
medicine.diagnostic_test
Cell Death
Calpain
Autophagy
Neurodegeneration
HSC70 Heat-Shock Proteins
medicine.disease
Cathepsins
Cell biology
030104 developmental biology
Neurology
Nerve Degeneration
biology.protein
Lysosomes
Biotechnology
Subjects
Details
- ISSN :
- 18729649
- Volume :
- 32
- Database :
- OpenAIRE
- Journal :
- Ageing research reviews
- Accession number :
- edsair.doi.dedup.....6fede4ec7735509c782771a6bb58e95b