Biomarkers for differential calpain activation in healthy and diseased brains: a systematic review

Abstract

Calpains refer to a family of intracellular non-lysosomal cysteine proteases. They are regulatory rather than digestive proteases because of limited substrate proteolysis. Activation of calpains at neutral pH distinguishes them from other cysteine proteases such as cathepsins. Most calpains have widespread distribution in various tissues of the body. The best-characterized isoforms μ-calpain and m-calpain are the predominant calpains in the central nervous system (CNS). At least in vitro, μ-calpain and m-calpain (a.k.a. calpain-1 and calpain-2) are activated by μM and nearly mM Ca2+ concentrations, respectively. Considering their numerous important functions in the CNS, identifying plausible biomarkers for calpain activation represents a major advancement for the diagnosis and treatment of brain diseases and for better understanding of their individual physiological roles. This is a challenging and complicated task as μ-calpain and m-calpain have overlapping substrate specificity and because the presence of substrate degradation products cannot distinguish between activation of these two calpains. Moreover, although substrate degradation products have been used as indicators (biomarkers) of calpain activation, it has been difficult to discriminate between those degraded by physiological or pathological processes that involve either one of the two isoforms. Further, the limited substrate cleavage under physiological conditions coupled to little prevalence of degradation products renders their detection more challenging. Indeed, aside from possible quantitative differences in the magnitude of degradation of any single substrate, it remains to be determined whether any specific degradation product can be used as a biomarker to point out physiological substrate cleavage and tell it apart from pathological degradation. In light of exciting new studies revealing phosphorylation-dependent activation of calpains published in the past few years this chapter reviews the patho.