RNAi knockdown of Par-4 inhibits neurosynaptic degeneration in ALS-linked mice

J Neurochem. 2005 Jan;92(1):59-71. doi: 10.1111/j.1471-4159.2004.02834.x.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amyotrophic Lateral Sclerosis / enzymology
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Animals
  • Apoptosis Regulatory Proteins
  • Cells, Cultured
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / physiology
  • Mice
  • Mice, Transgenic
  • Nerve Degeneration / enzymology
  • Nerve Degeneration / metabolism*
  • Nerve Degeneration / prevention & control
  • Neural Inhibition / genetics*
  • PC12 Cells
  • RNA Interference*
  • Rats
  • Superoxide Dismutase / biosynthesis
  • Superoxide Dismutase / genetics
  • Synapses / drug effects
  • Synapses / metabolism*

Substances

  • Apoptosis Regulatory Proteins
  • Intracellular Signaling Peptides and Proteins
  • prostate apoptosis response-4 protein
  • SOD1 G93A protein
  • Superoxide Dismutase