Effect of ozone exposure on Amyotrophic Lateral Sclerosis (ALS) pathology using a mice model of TDP-43 proteinopathy

Background Ozone (O3), one of the main photochemical pollutants in the atmosphere today, is a serious health risk factor. Although the effects of O3 exposure have been documented on many diseases, they have not yet been examined on Amyotrophic Lateral Sclerosis (ALS)- a fatal progressive and neurodegenerative disease. Objectives To investigate the effect of the O3 exposure in a mice model of TDP-43 proteinopathy, exploring a possible association between the O3 exposure and the ALS pathogenesis. Methods TDP-43A315T and wild-type (WT) mice were exposed to O3 (0.25 ppm) or filtered air (FA) for 15 days (4 hours/day). We assessed (1) weight loss (2) motor performance (3) plasma glucose content and (4) metabolic markers from plasma samples of the animals. Results Throughout the experiment, we observed a progressive decline in body weight and the motor coordination in TDP-43A315T mice compared to WT controls. Although there was a trend, there were no significant differences in the decline of body weight of TDP-43A315T mice when exposed to either FA or O3. In O3-TDP-43A315T mice, the disease duration lasted longer. In addition, O3-TDP-43A315T mice showed improvements in motor performance as well TDP-43A315T mice were hypoglycemic compared to WT mice. However, FA-TDP-43A315T mice showed lower plasma glucose levels at the disease end-stage. We found altered levels of adipokines and metabolic proteins in TDP-43A315T mice compared to WT controls. A positive correlation was found among GIP and glucagon compared to insulin concentrations in control mice. Interestingly, resistin, Gastric Inhibitory Peptide (GIP), Glucagon Like Peptide 1 (GIP-1) and insulin levels were higher in O3-TDP-43A315T mice. Discussion We provide new evidence about a mechanistic link between O3 exposure and the improvement of the metabolic disturbances present in TDP-43A315T mice. Further studies are needed to corroborate the obtained results as they warrant to understanding the underlying mechanisms. ### Competing Interest Statement The authors have declared no competing interest.