HYPOTHALAMIC MECHANISMS OF HIGH-CALORIE INTERVENTION IN AMYOTROPHIC LATERAL SCLEROSIS

​Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, with on average 2 to 5 years lifespan. Metabolic alterations are observed in ALS patients and ALS mouse models prior to the onset of motor symptoms, linked to dysregulated neuropeptides and atrophy of hypothalamus. High-fat diet (HFD) compensates weight loss and prolong survival in ALS mice and in fast-progressors patients but the underlying mechanisms are largely unknown. This study aims to illustrate a clearer ALS-associated hypothalamic gene profile and delve deeper into the HFD-related mechanisms in ALS metabolism. Single-cell RNA sequencing of hypothalamus was conducted in transgenic mice with different ALS gene mutations and their non-mutant littermates (control mice). Indirect calorimetry was performed in ALS mice and control mice after 30 days HFD. Body mass, ambulatory locomotion, energy expenditure, and respiratory exchange ratio were measured. Circadian patterns of these parameters were assessed using functional data analysis (FDA). Our results show that at pre-symptomatic stage, FUS^ΔNLS/+ mice showed less differentially expressed genes (DEGs) among the major cell types in hypothalamus than SOD1^G86R mice, while many of the DEGs of SOD1^G86R are related to energy metabolisms. Energy expenditure was lower in FUS^ΔNLS/+ mice compared to control mice during both light and dark cycle, but this defect was compensated by HFD. These results suggest that hypothalamic transcriptomic changes in ALS are shown before motor symptoms appear. HFD helps remedy metabolic deficiencies in ALS.