Potential Therapeutic Interventions Targeting NAD⁺ Metabolism for ALS

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons. While there have been many potential factors implicated for ALS development, such as oxidative stress and mitochondrial dysfunction, no exact mechanism has been determined at this time. Nicotinamide adenine dinucleotide (NAD⁺) is one of the most abundant metabolites in mammalian cells and is crucial for a broad range of cellular functions from DNA repair to energy homeostasis. NAD⁺ can be synthesized from three different intracellular pathways, but it is the NAD⁺ salvage pathway that generates the largest proportion of NAD⁺. Impaired NAD⁺ homeostasis has been connected to aging and neurodegenerative disease-related dysfunctions. In ALS mice, NAD⁺ homeostasis is potentially disrupted prior to the appearance of physical symptoms and is significantly reduced in the nervous system at the end stage. Treatments targeting NAD⁺ metabolism, either by administering NAD⁺ precursor metabolites or small molecules that alter NAD⁺-dependent enzyme activity, have shown strong beneficial effects in ALS disease models. Here, we review the therapeutic interventions targeting NAD⁺ metabolism for ALS and their effects on the most prominent pathological aspects of ALS in animal and cell models.