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Par-4: an emerging pivotal player in neuronal apoptosis and neuro-degenerative disorders.
Prostate apoptosis response-4 (Par-4) is a 38-kDa protein initially identified 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 apoptosis, including protein kinase Czeta, Bcl-2, and caspase-8.
A rapid increase 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 level, acts at an early stage of the apoptotic cascade prior to caspase activation and mitochondrial dysfunction.
The mechanism whereby Par-4 promotes apoptosis may involve inhibition of the antiapoptotic transcription factor NF-kappaB and suppression of Bcl-2 expression and/or function.
Studies of postmortem tissues from patients and animal models of neuro-degenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases, amyotrophic lateral sclerosis (ALS), and HIV encephalitis, have documented increased levels of Par-4 in vulnerable neurons.
Manipulations 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.
Interestingly, Par-4 levels rapidly increase in synaptic terminals following various insults, and such local increases in Par-4 levels appear to play important roles in synaptic dysfunction and degeneration.
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 neuro-degenerative disorders.
J Mol Neurosci 1999 Aug-Oct;13(1-2):17-30
Mattson MP, Duan W, Chan SL, Camandola S
University of Kentucky, Lexington, Kentucky, 40536, USA.
PMID: 10691289, UI: 20153148
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=10691289&form=6&db=m&Dopt=b>
janet paterson
52 now / 41 dx / 37 onset
a new voice: http://www.geocities.com/janet313/
613 256 8340 PO Box 171 Almonte Ontario Canada K0A 1A0
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