Apoptosis and Caspaces in neurodegenerative diseases

Friedlander RM. Mechanisms of disease. NEJM 2003; 348:1365-1375.

Caspaces (cysteine dependent, apartate specific proteases) are the executioners in the apoptotic programs for cell death. This work was originated in nematodes and has become prominent in the past fifteen years only. There are upstream or initiator caspaces and downstream executioner caspaces. Cytochrome c, a part of the electron transport chain, is intimately involved . There also are inhibitors of caspaces to prevent apoptosis gone amuk.

In acute neurologic diseases, necrotic death and apoptosis both occur. In neurodegenerative diseases, apoptosis predominates. Caspaces may be important in AD, PD, HIV related dementia. In addition, a role exists in ALS mice, in which caspace 1 and 3 are upregulated. 10 % of patients have a SOD mutation and in these it may be preordinant. In Huntington's disease, huntingten is depleted which is a substrate for caspace 1. Increased caspace mediated cleavage of huntingten leads to hgih levels of huntingten fragments and depleted wild type huntingten. Down regulation of receptors also occurs, and this is caspace dependent but not considered apoptosis.

Minocycline inhibits nitric oxide and reduces the severity of ischemia induced tissue injury. It also inhibits caspace. Neuroprotection with it has been observed in models of HD, ALS, brain injury, PD and MS. The mechanism is the direct inhibition of the release of cytochrome c, and inhibition of downstream activation of caspace 3. It is orally bioavailable, crosses the bloodbrain barrier is safe, and is being tested in HD and ALS.

Apoptosis is "contagious" as it occurs, as it releases pro-apoptotic factors causing neighborhood to all commit apoptosis It is therefore a reasonable idea for treatment of acute neurologic disease as well.