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.

Neuroprotection in the peripheral nervous system

Hoke A. Neuroprtoection in the peripheral nervous system. Arch Neurol 2006; 63: 1681-1685

The authors criticise the dogma holding that there is a "dying back " neuropathy in which the axon degrades centripetally from the end. In other work (Griffin and Hoke) the concept of last field of irrigation is reversed, and neuronal body depends upon target derived growth factors for survival. Also, Raff et al proposed that the so-called dying back neuropathy is a programmed responsed similar to apoptosis. Neuroprotective activities designed for neuronal survival, such as in the brain or spinal cord, may be inappropos due to lack of significant neuronal death in many peripheral neuropathies. The author proposes research center on 2 areas: mechanisms involving distal axonal degeneration, and axon-glia mechanisms important for neuroprotection.

Unlike Wallerian degeneration, in many peripheral neuropathies there is compartmental degeneration of axons without physical compartmentalization. In HIV virus envelope gp120 involves chemokine receptors on Schwann cells. In familial ALS, mutations in the SOD 1 gene suggested initial ep abnormality was explained by axonal degeneration not neuronal loss.

In stroke literature ischemic preconditioning protects neurons and limits damage from future events. This endogenous protection may be related to astrocyte secreted erythropoietin. In sciatic transection in rats, Schwann cells in contact upregulate erythropoetin expression and DRG ensory neurons upregulate receptors for the same. The injury signal in nitric oxide, that activates hypoxia-inducible-factor 1 that induces erythropoetin changes. Exogenous erythropoietin helps in models of neuropathy due to paclitaxel, diabetic neuropathy, and cisplatinum induced PN.

The authors also note a mouse strain that is resistant to degeneration after injury, due to a Wlds gene (Wallerian degeneration-slow). Further studies of axon-glia interactions are needed.