OBJECTIVE: Mitochondrial dysfunction is one of the earliest pathological events observed in amyotrophic lateral sclerosis (ALS). The aim of this study is to evaluate the therapeutic efficacy of 2,4-dinitrophenol (DNP), a mild mitochondrial uncoupler, in an ALS mouse model to provide preclinical proof-of-concept evidence of using DNP as a potential therapeutic drug for ALS. METHODS: hSOD1 RESULTS: DNP delayed disease onset
improved motor coordination and muscle performance in vivo
preserved muscle contractile function, neuromuscular junction morphology, and muscle innervation
and reduced inflammation and protein oxidation at 18 weeks old in hSOD1 INTERPRETATION: Our results strongly support that micro-dose DNP may be used as a potential novel treatment for ALS patients, with a possibility for recovery, when used at optimal doses and time of intervention. ANN NEUROL 2025
97:542-557.