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The prostate apoptosis response-4 protein participates in motor neuron degeneration in amyotrophic lateral sclerosis

WARD A. PEDERSEN^*, HONG LUO^*, INNA KRUMAN^*, EDWARD KASARSKIS and MARK P. MATTSON^*,§1

^* Sanders-Brown Research Center on Aging,
Department of Neurology, and Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky 40536, USA; and
^§ Laboratory of Neurosciences, National Institute on Aging, Baltimore, Maryland 21224, USA

¹Correspondence: Laboratory of Neurosciences, National Institute on Aging, GRC 4F01, 5600 Nathan Shock Drive, Baltimore, MD, 21224, USA. E-mail: mattsonm{at}grc.nia.nih.gov

Prostate apoptosis response-4 (Par-4), a protein containing a leucine zipper domain within a death domain, is up-regulated in prostate cancer cells and hippocampal neurons induced to undergo apoptosis. Here, we report higher Par-4 levels in lumbar spinal cord samples from patients with amyotrophic lateral sclerosis (ALS) than in lumbar spinal cord samples from neurologically normal patients. We also compared the levels of Par-4 in lumbar spinal cord samples from wild-type and transgenic mice expressing the human Cu/Zn-superoxide dismutase gene with a familial ALS mutation. Relative to control samples, higher Par-4 levels were observed in lumbar spinal cord samples prepared from the transgenic mice at a time when they had hind-limb paralysis. Immunohistochemical analyses of human and mouse lumbar spinal cord sections revealed that Par-4 is localized to motor neurons in the ventral horn region. In culture studies, exposure of primary mouse spinal cord motor neurons or NSC-19 motor neuron cells to oxidative insults resulted in a rapid and large increase in Par-4 levels that preceded apoptosis. Pretreatment of the motor neuron cells with a Par-4 antisense oligonucleotide prevented oxidative stress-induced apoptosis and reversed oxidative stress-induced mitochondrial dysfunction that preceded apoptosis. Collectively, these data suggest a role for Par-4 in models of motor neuron injury relevant to ALS.—Pedersen W. W., Luo H., Kruman, I., Kasarskis, E., Mattson, M. P. The prostate apoptosis response-4 protein participates in motor neuron degeneration in amyotrophic lateral sclerosis.

Key Words: NSC-19 • oxidative stress • spinal cord • superoxide dismutase • transgenic mice

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