Retinoid signaling alterations in amyotrophic lateral sclerosis.

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.