Biology subjects

Ferrer-Donato, A.

Publications and source records attributed to Ferrer-Donato, A..

4 recordsLinked to original sources

bioRxiv2025

Sex-specific hypothalamic axis disruption in the rNLS8 mouse model of amyotrophic lateral sclerosis (ALS)

Sex-related differences have gained increasing attention in recent years due to evidence of varying prevalence, pathophysiology, survival rates, and disease progression between males and females in amyotrophic lateral sclerosis (ALS). Differences in brain metabolism between sexes in ALS patients have also been reported; however, the specific molecular mechanisms remain poorly understood. As growing evidence supports a strong metabolic component in ALS, this study investigates alterations in leptin, one of the key regulators of metabolism, that is known to be altered during ALS progression in rNLS8 mice, a transgenic mouse model of ALS which closely recapitulates the TAR DNA-binding protein (TDP-43) pathology observed in most patients with ALS. We also examined changes in hypothalamic neuronal genes involved in metabolic regulation through food intake in rNLS8 mice. Additionally, pathological alterations in the spinal cord, a primary site of ALS pathology, were also assessed. Using molecular biology techniques we analysed the expression levels of leptin, its long receptor (Ob-Rb), and its downstream signaling pathways (Akt and STAT3) in rNLS8 mice compared to age- and sex-matched wild-type littermates. Our results revealed significant sex- and disease stage-dependent differences in leptin and Ob-Rb expression in white adipose tissue and the hypothalamus, along with increased activation of the Akt signaling pathway in the spinal cord of rNLS8 mice. These findings suggest that ALS progression differs by sex in rNLS8 mice, which may impact overall disease progression and the effectiveness of potential therapeutic interventions targeting metabolism, such as nutritional strategies that influence leptin levels.

neuroscience↗

bioRxiv2025

White adipose tissue undergoes pathological dysfunction in the TDP-43A315T mouse model of amyotrophic lateral sclerosis (ALS)

White adipose tissue (WAT) has a crucial role in maintaining systemic energy homeostasis. Numerous biological pathway studies have highlighted the importance of adipokines in regulating metabolic pathways and contributing to metabolic dysfunction in animal models and patients with ALS. Despite these associations, the specific molecular mechanisms remain poorly understood. Moreover, the direct contribution of WAT to the energy metabolism abnormalities observed in ALS has yet to be clearly defined. The current study sought to identify perturbances in WAT, main source of leptin, during the clinical course of the disease in TDP-43A315T mice using histological, proteomic, and molecular biological techniques. We present the first evidence of a significant histological alteration in WAT prior to the symptomatic stage of the disease in TDP-43A315T mice, providing novel insights into pathological features earlier in the onset of symptoms, and showing WAT as a target organ for ALS. In human ALS cases, we found that circulating leptin levels at the time of diagnosis were lower in the plasma of men with ALS who were overweight or obese and had rapidly progressive ALS, emphasizing the importance of considering sex-specific approaches when analysing adipokines essential for body weight control.

neuroscience↗

bioRxiv2021

Alterations in leptin signaling in Amyotrophic Lateral Sclerosis (ALS)

Leptin has been suggested to play a role in amyotrophic lateral sclerosis (ALS), a fatal progressive and neurodegenerative disease. This adipokine has previously been shown to be associated with a lower risk of ALS disease and to confer a survival advantage in ALS patients. However, the role of leptin in the progression of ALS is unknown. Indeed, our understanding of the mechanisms underlying leptins effects in the pathogenesis of ALS is very limited, and it is fundamental to determine whether alterations in leptins actions take place in this neurodegenerative disease. To characterize the association between leptin signaling and the clinical course of ALS we assessed the mRNA and protein expression profiles of leptin, the long leptin receptor (Ob-Rb) and leptin-related signaling pathways over the time course of the disease (onset and end-stage of disease), in TDP-43A315T mice compared to age-matched WT littermates. In addition, at the selected time-points immunoassay analysis was conducted to characterize plasma levels of total ghrelin, the adipokines (resistin and leptin) and metabolic proteins (plasminogen activator inhibitor type 1 (PAI-1), gastric inhibitory peptide (GIP), glucagon like peptide 1 (GLP-1), insulin and glucagon) in TDP-43A315T mice compared to WT controls. Our results indicate alterations in leptin signaling in the spinal cord and the hypothalamus on the backdrop of TDP-43-induced deficits in mice, providing new evidence about the pathways that could link leptin signaling to ALS.

neuroscience↗

bioRxiv2021

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

BackgroundOzone (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. ObjectivesTo 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. MethodsTDP-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. ResultsThroughout 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. DiscussionWe 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.

neuroscience↗