Ozone modified hypothalamic signaling enhancing thermogenesis in the TDP-43A315T transgenic model of Amyotrophic Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS), a devastating progressive neurodegenerative disease, has no effective treatment. Recent evidence supports a strong metabolic component in ALS pathogenesis. Indeed, metabolic abnormalities in ALS correlate to disease susceptibility and progression, raising additional therapeutic targets against ALS. Ozone (O3), a natural bioactive molecule, has been shown to elicit beneficial effects to reduce metabolic disturbances and improved motor behavior in TDP-43A315T mice. However, it is fundamental to determine the mechanism through which O3 acts in ALS. To characterize the association between O3 exposure and disease-associated weight loss in ALS, we assessed the mRNA and protein expression profile of molecular pathways with a main role in the regulation of the metabolic homeostasis on the hypothalamus and the brown adipose tissue (BAT) at the disease end-stage, in TDP-43A315T mice compared to age-matched WT littermates. In addition, the impact of O3 exposure on the faecal bacterial community diversity, by Illumina sequencing, and on the neuromuscular junctions (NMJs), by confocal imaging, were analysed. Our findings suggest the effectiveness of O3 exposure to induce metabolic effects in the hypothalamus and BAT of TDP-43A315T mice and could be a new complementary non-pharmacological approach for ALS therapy.