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Am J Neurodegener Dis 2012;1(2):130-145

Original Article
Retinoid signaling alterations in amyotrophic lateral sclerosis

Christi L Kolarcik, Robert Bowser

Department of Pathology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA USA; Divisons
of Neurology and Neurobiology, Barrow Neurological Institute, 350 W Thomas Rd, Phoenix, AZ 85013 USA.

Received July 3, 2012; accepted July 21, 2012; Epub July 23, 2012; published July 31, 2012

Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease for which effective therapeutic
interventions and an understanding of underlying disease mechanism are lacking.  A variety of biochemical pathways
are believed to contribute to the pathophysiology of ALS that are common to both sporadic and familial forms of the
disease.  Evidence from both human and animal studies indicates that expression of retinoid signaling genes is
altered in ALS and may contribute to motor neuron loss.  Our goals were to examine the expression and distribution of
proteins of the retinoid signaling pathway in spinal cord samples from patients with sporadic and familial ALS and to
evaluate the role of these proteins in motor neuron cell survival.  In sporadic ALS, the cytoplasmic binding protein that
facilitates nuclear translocation of retinoic acid, cellular retinoic acid binding protein-II (CRABP-II), was localized to the
nucleus and retinoic acid receptor β (RARβ) was significantly increased in motor neuron nuclei when compared to
either familial ALS patients or non-neurologic disease controls.  Motor neurons with increased nuclear RARβ were
negative for markers of apoptosis.  Pre-treatment of primary motor neuron-enriched cultures with a pan-RAR or RARβ-
specific agonist decreased motor neuron cell death associated with oxidative injury/stress while a RARβ-specific
antagonist enhanced cell death.  Our data suggest retinoid signaling is altered in ALS and increased nuclear RARβ
occurs in motor neurons of sporadic ALS patients.  Activation of RARβ protects motor neurons from oxidative-induced
cell death. (AJND1207001)

Keywords: Retinoid signaling, retinoic acid receptors, nuclear receptor, amyotrophic lateral sclerosis, motor neurons,
oxidative stress-induced cell death, motor neuron


Address all correspondence to:
Robert Bowser, PhD
Division of Neurology and Neurobiology,
Barrow Neurological Institute
350 W Thomas Road, Phoenix, AZ, USA.
E-mail: Robert.Bowser@DignityHealth.org