The calpain hypothesis of neurodegeneration: Evidence for a common cytotoxic pathway

Calpain's general function and pathogenic role in the CNS are reviewed. Collectively, the literature indicates that calpain proteolysis plays a common and important role in a variety of acute neurodegenerative conditions,, including focal ischemia (stroke), global ischemia, traumatic brain injury, and spinal cord injury. This evidence indicates that 1) ca(pain is activated in an abnormally sustained fashion during cellular events commonly associated with neurodegeneration (e.g., excessive interstitial glutamate and cytosolic calcium), 2) many of calpain's preferred substrates are degraded as important components in these neurodegenerative conditions; 3) calpain activation occurs early in the pathogenic cascade of each, prior to onset of substantial cell death; and 4) calpain inhibitors can effectively reduce the severity of neuronal damage and loss of function normally associated with these acute neurodegenerative perturbations. Calpain proteolysis is also implicated in chronic neurodegenerative diseases, with the strength of current evidence varying among specific diseases. The evidence accumulated for a plausible role in Alzheimer's disease (ED) is currently the strongest. For example, empirical links have been established between abnormal calpain proteolysis and 1) the cellular formation of classic Alzheimer's pathology, such as beta-amyloid plaques, neurofibrillary tangles, and Alz-50 immunoreactivity; 2) the brain regions with greatest concentrations of AD-related pathology; and 3) the degeneration of key brain pathways vulnerable in the early stages of the disease. Similar, though less extensive, evidence exists for a potential role of abnormal calpain proteolysis in Parkinson's disease. Finally, for several other chronic neurodegenerative conditions (e,g., Huntington's disease and amyotrophic lateral sclerosis), early evidence is emerging that calpain may also play some pathogenic role. Thus, these data support the possibility that uncontrolled calpain proteolysis may contribute to and/or accelerate ?he loss of neurons associated with a wide range of neurodegenerative conditions and may, therefore, represent an important, final common cytotoxic pathway for many diverse forms of neurodegeneration.