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Prostate apoptosis response-4 (Par-4): an emerging target for Alzheimer’s and Parkinson’s diseases and stroke

Alzheimer’s disease (AD), Parkinson’s disease (PD) and stroke are neurodegenerative disorders that are increasing in prevalence as life expectancy increases worldwide. Each of these disorders is characterised by the degeneration of neurones in certain brain regions, and by a similar biochemical cascade of events that results in a form of cell death called apoptosis. Par-4 was initially identified as the product of a gene upregulated in prostate tumour cells undergoing apoptosis. Par-4 contains both a death domain and a leucine zipper domain, and has been shown to interact with several proteins known to modulate apoptosis, including protein kinase Cζ (PKCζ), Bcl-2 and caspases. Studies of post-mortem tissues from patients with AD, and animal models of AD, PD and stroke, have documented increased levels of Par-4 in vulnerable neurones prior to their demise. Treatments that block Par-4 expression or function prevent neuronal cell death in models of each disorder, suggesting a critical role for Par-4 in the neurodegenerative process A better understanding of the molecular and cellular biology of Par-4 will help clarify mechanisms of neuronal apoptosis, and may lead to the development of novel preventative and therapeutic strategies for neurodegenerative disorders.