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RNAi knockdown of Par‐4 inhibits neurosynaptic degeneration in ALS‐linked mice
Author(s) -
Xie Jun,
Awad Keytam S.,
Guo Qing
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02834.x
Subject(s) - gene knockdown , rna interference , neuronal degeneration , microbiology and biotechnology , degeneration (medical) , biology , chemistry , gene , medicine , genetics , rna , pathology , disease
Evidence from human amyotrophic lateral sclerosis (ALS) patients and ALS‐linked Cu/Zn superoxide dismutase (Cu/Zn‐SOD) transgenic mice bearing the mutation of glycine to alanine at position 93 (G93A) suggests that the pro‐apoptotic protein prostate apoptosis response‐4 (Par‐4) might be a critical link in the chain of events leading to motor neuron degeneration. We now report that Par‐4 is enriched in synaptosomes and post‐synaptic density from the ventral horn of the spinal cord. Levels of Par‐4 in synaptic compartments increased significantly during rapid and slow declining stages of muscle strength in hSOD1 G93A mutant mice. In the pre‐muscle weakness stage, hSOD1 G93A mutation sensitized synaptosomes from the ventral horn of the spinal cord to increased levels of Par‐4 expression following excitotoxic and apoptotic insults. In ventral spinal synaptosomes, Par‐4‐mediated production of pro‐apoptotic cytosolic factor(s) was significantly enhanced by the hSOD1 G93A mutation. RNA interference (RNAi) knockdown of Par‐4 inhibited mitochondrial dysfunction and caspase‐3 activation induced by G93A mutation in synaptosomes from the ventral horn of the spinal cord, and protected spinal motor neurons from apoptosis. These results identify the synapse as a crucial cellular site for the cell death promoting actions of Par‐4 in motor neurons, and suggest that targeted inhibition of Par‐4 by RNAi may prove to be a neuroprotective strategy for motor neuron degeneration.