Prostate apoptosis response-4 production in synaptic compartments following apoptotic and excitotoxic insults: Evidence for a pivotal role in mitochondrial dysfunction and neuronal degeneration

Synapses are often located at great distances from the cell body and so mus t be capable of transducing signals into both local and distant responses. Although progress has been made in understanding biochemical cascades invol ved in neuronal death during development of the nervous system and in vario us neurodegenerative disorders, it is not known whether such cascades funct ion locally in synaptic compartments. Prostate apoptosis response-4 (Par-4) is a leucine zipper and death domain-containing protein that plays a role in neuronal apoptosis. We now report that Par-4 levels are rapidly increase d in cortical synaptosomes and in dendrites of hippocampal neurons in cultu re and in vivo, following exposure to apoptotic or excitotoxic insults. Par -4 expression is regulated at the translational level within synaptic compa rtments. Par-4 antisense treatment suppressed mitochondrial dysfunction and caspase activation in synaptosomes and prevented death of cultured hippoca mpal neurons following exposure to excitotoxic and apoptotic insults. Local translational regulation of death-related proteins in synaptic compartment s. may play a role in programmed cell death, adaptive remodeling of synapse s, and neurodegenerative disorders.