Alteraciones en el metabolismo energético y lipídico asociadas a la pérdida de función de TDP-43: Implicación de mecanismosno-neuronales en la Esclerosis Lateral Amiotrófica

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative diseasecharacterized by the progressive loss of upper and lower motor neurons (MNs),leading to muscle weakness, atrophy, and eventually paralysis andrespiratory failure. A central pathological feature of ALS is TDP-43proteinopathy, which involves both the loss of nuclear function and theaggregation of TDP-43 in the cytoplasm. TDP-43 primarily regulates RNAmetabolism and stress granules, while also playing a role in maintainingcellular energy homeostasis. Given the high energy demands of MNs, they dependheavily on metabolic support from surrounding cells, including glial cell inthe central nervous system and muscle cells in the periphery. It ishypothesized that disruptions in the metabolic cross-talk between these cellscan impair energy balance and contribute to MN dysfunction.

This PhD thesis explores the impact of TDP-43 loss-of-function oncellular metabolism in cultured astrocytes and skeletal muscle cells, with aparticular emphasis on lipid catabolism. Given that neurons lack mechanisms forutilizing lipids as an energy source, understanding how TDP-43 dysfunctionaffects lipid metabolism in supporting cells is crucial. Using metabolic fluxanalysis, lipidomics, transcriptomics, and live-cell imaging, we identifiedsignificant metabolic disruptions: in addition to general alterations inglycolysis and mitochondrial respiration in TDP-43-deficient astrocytes andmuscle cells, we observed specific disruptions in fatty acid oxidation (FAO),leading to chronic AMPK activation as a compensatory mechanism attempting torestore cellular energy balance. Furthermore, we found defective intronretention of the FAO enzyme ACADVL in both astrocytes and muscle cells -whichis not reported in neurons-, potentially explaining the FAO defects andsubsequent lipid accumulation. Pharmacological induction of FAO via ACC2inhibition improved myogenic capacity in TDP-43-silenced myoblasts, though theprecise mechanisms remain unclear. Our findings suggest that metabolicdysfunction and lipotoxicity in non-neuronal cells driven by TDP-43 pathology maycontribute to non-cell-autonomous MN toxicity in ALS, positioning lipidhomeostasis as a promising therapeutic target.