RNAi knockdown of Par-4 inhibits neurosynaptic degeneration in ALS-linked mice.
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.
Xie
Jun
J
Department of Physiology, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
Awad
Keytam S
KS
Guo
Qing
Q
D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002478:Cells, Cultured; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000201:enzymology / Q000378:metabolism* / Q000517:prevention & control; D009433:Neural Inhibition / Q000235:genetics*; D016716:PC12 Cells; D034622:RNA Interference; D051381:Rats; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; C101296:prostate apoptosis response-4 protein; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase