Apoptosis neurodegenerative disorders

Excessive apoptosis Neurodegenerative disorders (Alzheimers s disease, Parkinson s disease), hematological disorders, autoimmune disorders (graft versus host disease, type 1 diabetes, rheumatoid arthritis), ischemia, heart failure, inflammation, osteoarthritis, human immunodeficiency virus, bacterial infections, allograft rejection, trauma. 

Mechanisms of Neuronal Death in Neurodegenerative Disorders General Concepts 347 Apoptosis 348... 

Bcl-2 B cell lymphoma protein 2 (Bcl-2) is a family of proteins that regulate apoptosis (programmed cell death). Apoptosis is a necessary process whereby aged or damaged cells are replaced by new cells. Dysfunction of the apoptosis process results in disease inhibition of apoptosis results in cancer, autoimmune disorder, and viral infection, whereas increased apoptosis gives rise to neurodegenerative disorders, myelodysplastic syndromes, ischemic injury, and toxin-induced liver disease. 

Increasing evidence suggests that members of the Bcl-2 family may act not only at the mitochondrial levels but also at the ER level. There is work that suggests that Bak and Bax are involved in controlling Ca " " homeostasis in the ER because double knock-out mice for Bax and Bak exhibit impaired Ca " efflux from the ER and uptake by the mitochondria this is correlated with low levels of apoptotic cell death (Nutt et al., 2002b, a). The relevance of these data to human neurodegenerative disorders is not yet clear because so far only caspase-12 has been reported to become activated after ER stress-induced apoptosis. There is evidence showing that both Bax... 

Bcl-2 family proteins are attractive targets for drug development. Conceivably, inhibitors of the pro-apoptotic members would block apoptosis prior to cytochrome c release and caspase activation and may have therapeutic value for conditions that appear to involve excess apoptosis (e.g., neurodegenerative disorders and ischemia associated with stroke and heart attack). Activators of the pro-apoptotic members or inhibitors of the anti-apoptotic members would have value in treating disorders that appear to progress as a result of too little apoptosis (e.g., cancer and autoimmunity). 

Apoptosis has been implicated in delayed neuronal death associated with many neurodegenerative disorders such as Parkinson s disease, stroke, Huntington s disease, traumatic head injury, Alzheimer s disease, motor neuron degeneration, spinal cord injury, and multiple sclerosis. Since an extensive description of the role of apoptosis in each of these disorders is beyond the scope of the present text, we shall focus on anti-apoptotic strategies for stroke, Parkinson s disease, and multiple sclerosis. 

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