Retinoid receptor‐mediated signaling in motor neurons and its implications for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is defined by progressive degeneration and death of upper and lower motor neurons. Recent work indicates retinoid signaling may contribute to the disease process. Nuclear retinoic acid receptors (RARs) are ligand‐activated transcription factors activated by all‐ trans retinoic acid (ATRA); they mediate gene expression by forming heterodimers with retinoid X receptors (RXRs). We investigated the effects of RAR‐mediated signaling on motor neuron survival, morphology and downstream gene expression. Motor neuron‐enriched cultures established from embryonic day 14 rats were treated with pan‐agonists, pan‐antagonists and isotype‐specific agents. Toxicity studies were performed in the presence or absence of either hydrogen peroxide (to model oxidative stress/injury) or glutamate (to model excitotoxicity). In the presence of ATRA, the number of branch points/cell was decreased in motor neurons. RARalpha was localized to proximal and distal processes; RARbeta was localized to the cell body and nucleus. When ATRA was administered in the presence of toxin, motor neuron cell death was delayed. Signaling through RARs appears to maintain long neurites with less branching and delays toxin‐induced cell death. As we have observed increased nuclear RARbeta in sporadic ALS patients, downstream genes modulated by RARbeta are currently being characterized. Research Support: NIH grant ES013469 (RB); NIH T32 EB001026 (CK); NIH T32 05 TL1 RR024155‐02 (CK)