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

Title

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

Creator

Xie J; Awad K S; Guo Q

Publisher

Journal of Neurochemistry

Date

2005
2005-01

Description

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.

Subject

amyotrophic lateral sclerosis; amyotrophic lateral sclerosis; anterior horn; antisense oligonucleotides; apoptosis; apoptosis response-4; Biochemistry & Molecular Biology; cells; Cu/Zn superoxide dismutase; motor-neuron degeneration; neurons; Neurosciences & Neurology; prostate; protein; RNA interference; sod1; spinal motor neurons; synapse; synapses; transgenic mouse model

Format

Journal Article

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Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

59-71

Issue

1

Volume

92

Citation

Xie J; Awad K S; Guo Q, “RNAi knockdown of Par-4 inhibits neurosynaptic degeneration in ALS-linked mice,” NEOMED Bibliography Database, accessed May 18, 2021, https://neomed.omeka.net/items/show/7624.

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