Recent developments in the therapeutic targeting of calpains in neurodegeneration

Abstract

The calpain–calpastatin system is distinguished from dozens of other proteolytic processing pathways in the cell by its dependence on calcium (Ca²⁺) and redox state and by the limited nature of its endoproteolytic processing. It is also a major focus in diseases and conditions of the CNS. Calpain-dependent hypo- or hyper-processing of pathologically linked substrates has been implicated in the etiology of Alzheimer's, Parkinson's and Huntington's diseases, as well as the family of transmissible spongioform encephalopathies (TSEs). Calpain also contributes to injury-related neuronal death/dysfunction of both the brain (TBI) and spinal cord (SCI) and appears to be a contributing factor in multiple sclerosis. Because calpain is linked to such a broad range of neurodegenerative conditions and diseases that affect millions of people worldwide, there is a clear need to develop tools to modulate its proteolytic activity.

Keywords::

• Alzheimer's disease
• calcium
• calpastatin
• CNS
• Huntington's disease
• multiple sclerosis
• oxidative stress
• Parkinson's disease
• redox
• spinal cord injury
• transmissible spongioform encephalopathies
• traumatic brain injury