Calpain is a ubiquitous calcium-sensitive protease that is essential for normal physiologic neuronal function. However, alterations in calcium homeostasis lead to persistent, pathologic activation of calpain in a number of neurodegenerative diseases. Pathologic activation of calpain results in the cleavage of a number of neuronal substrates that negatively affect neuronal structure and function, leading to inhibition of essential neuronal survival mechanisms. In this review, we examine the mechanistic underpinnings of calcium dysregulation resulting in calpain activation in the acute neurodegenerative diseases such as cerebral ischemia and in the chronic neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, prionrelated encephalopathy, and amylotrophic lateral sclerosis. The premise of this paper is that analysis of the signaling and transcriptional consequences of calpain-mediated cleavage of its various substrates for any neurodegenerative disease can be extrapolated to all of the neurodegenerative diseases vulnerable to calcium dysregulation.

We examined spinal cord sections from Guamanian Chamorros with or without amyotrophic lateral sclerosis or parkinsonism-dementia complex using immunohistochemistry and antibodies to epitopes that span the length of tau to characterize the tau epitope profile of neurofibrillary tangles in these spinal cords. Most (16/20) spinal cords, including some from Chamorros without documented clinical disease, contained tangles with a tau epitope profile similar to the tangles found in the forebrain and brain stem of these patients.

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