Journal
CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS
Volume 7, Issue 3, Pages 295-304Publisher
BENTHAM SCIENCE PUBL
DOI: 10.2174/187152708784936644
Keywords
Glaucoma; calpain; trabecular meshwork; isolevuglandin; lipid oxidation; posttranslational modifications; neuroprotection
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Funding
- National Glaucoma Research Program of American Health Assistance Foundation
- NIH [EY015266, GM021249]
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Glaucoma is a group of irreversible blinding eye diseases affecting over 70 million people worldwide. Systemic delivery of calpain-1 inhibitors was proposed as a neuroprotection strategy for the prevention of progressive optic nerve damage in glaucoma. We present a general review of calpain-1 and an account of vast differences in processing of calpain-1 in the trabecular meshwork (TM) and the optic nerve. Calpain-1 accumulates in the glaucomatous TM tissues in vivo. However, calpain-1 activity is substantially lower in the glaucomatous TM compared to controls, apparently owing to partial degradation, and modification by lipid oxidation products such as iso [4] levuglandin E2 (iso [4] LGE(2)). Treatment of calpain-1 with iso [4] LGE(2) in vitro results in covalent modification, inactivation, and resistance to protease digestion. Iso [4]LGE(2)-modified calpain-1 appeared to undergo ubiquitination in the TM by cellular degradation machinery mediated by ubch1-2, ubch5,6 and E6-AP, E2 and E3 enzymes respectively. In the TM, iso [4] LGE(2)-modified calpain-1 loading impairs the cellular proteasome activity consistent with competitive inhibition and formation of suicidal high molecular weight aggregates. In contrast, higher calpain-1 activity, that appears to be under translational control, was observed in glaucomatous optic nerve compared to control. Therapeutic neuroprotection strategies using calpain-1 inhibitors will require consideration of such anatomic differences in its activity and biosynthesis.
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