Retinoids and motor neuron disease: Potential role in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons (MN). This fatal disease is characterized by progressive muscular atrophy and unfortunately it does not have an effective treatment. Although a small proportion of ALS cases have a familiar origin, the vast majority of them are thought to have a sporadic origin. Although the pathogenesis of ALS has not been fully elucidated, various disorders in different cellular functions such as gene expression, protein metabolism, axonal transport and glial cell disorders have been linked to MN degeneration. Among them, proteostasis is one of the best studied. Retinoids are vitamin A-derived substances that play a crucial role in embryogenesis, development, programmed cell death and other cellular functions. Retinoid agonists behave as transcription factors throughout the activation of the nuclear retinoid receptors. Several reports in the literature suggest that retinoids are involved in proteostasis regulation, by modulating its two major pathways, the ubiquitin-proteasome system and the autophagy-lysosome response. Additionally, there are some evidences for a role of retinoids themselves, in ALS pathogenesis. In this review, we discuss the importance of proteostasis disruption as a trigger for MN degeneration and the capability of retinoids to modulate it, as well as the potential therapeutic role of retinoids as a new therapy in ALS.

Keywords: Amyotrophic lateral sclerosis; Bexarotene; Neurodegeneration; Retinoids; SOD1.

Fig. 1

Retinoid metabolism. Retinoid receptors are specifically associated to those genes which have a retinoid acid response element (RARE). This element is usually located at the promoter region. Normally retinoid receptors are inactivated, since they are associated to a group of molecules which act as transcription repressors. Once in the cell, retinoids through the action of different cellular retinoid acid binding proteins (CRABPs) can be stored or delivered to the nucleus activating the retinoid pathways. In the presence of ligand the dimeric nuclear receptor activates and changes its structural conformation, thus liberating from the inhibitor complex and promoting the transcription of its target genes. Many genes are modulated by retinoids. Among them there are genes involved in proteostasis, the antioxidant response, the intracellular signaling, the synaptic homeostasis and the inflammation.

Fig. 2

Neuroprotective effect of retinoids in ALS. This figure illustrates the main mechanisms involved in the pathogenesis of the SOD1G^93A murine model of ALS (A). Among them, disorders in gene expression, chromatolysis and mitochondrial alterations (m), vacuolar degeneration (Vc), ubiquitin-proteasome (UPS) system collapse with appearance of intracellular aggregates (U) and astrogliosis with perisomatic synaptic (pS) alterations seem to be some of the most important ones. Our investigations showed that treatment with the retinoid agonist bexarotene, had a beneficial effect at multiple levels (B). This retinoid helped to modulate gene expression, and delayed the protein synthesis machinery disruption and consequently decreased mitochondrial alterations and vacuolar degeneration. Additionally it reduced the intracellular aggregates. Bxt also preserved MN environment until more advanced stages.