Par-4 - An emerging pivotal player in neuronal apoptosis and neurodegenerative disorders

Prostate apoptosis response-4 (Par-4) is a 38-kDa protein initially identif ied as the product of a gene upregulated in prostate tumor 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 apo ptosis, including protein kinase C zeta, Bcl-2, and caspase-8. A rapid incr ease in Par-4 levels occurs in neurons undergoing apoptosis in a variety of paradigms, including trophic factor withdrawal, and exposure to oxidative and metabolic insults. Par-4, which can be induced at the translational lev el, acts at an early stage of the apoptotic cascade prior to caspase activa tion and mitochondrial dysfunction. The-mechanism whereby Par-4 promotes ap optosis may involve inhibition of the antiapoptotic transcription factor NF -kappa B and suppression of Bcl-2 expression and/or function. Studies of po stmortem tissues from patients and animal models of neurodegenerative disor ders, including Alzheimer's, Parkinson's, and Huntington's diseases, amyotr ophic lateral sclerosis (ALS), and HIV encephalitis,have documented increas ed levels of Par-4 in vulnerable neurons. Manipulations that block Par-4 ex pression or function prevent neuronal cell death in models of each disorder , suggesting a critical role for Par-4 in the neurodegenerative process Int erestingly, Par-4 levels rapidly increase in synaptic terminals following v arious insults, and such local increases in Par-4 levels appear to play imp ortant roles in synaptic dysfunction and degeneration. A better understandi ng of the molecular and cellular biology of Par-4 will help clarify mechani sms of neuronal apoptosis, and may lead to the development of novel prevent ative and therapeutic strategies for neurodegenerative disorders.