Regulation of lipid and redox metabolism in X-linked Adrenoleukodystrophy (X-ALD): therapeutic implications
[eng] X-linked adrenoleukodystrophy (X-ALD) is a rare neurometabolic disease characterized by the loss of function of the peroxisomal transporter ABCD1, which leads to an accumulation of very long-chain fatty acids (VLCFA), inducing the production of mitochondrial reactive oxygen species. Clinical p...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/179897 |
| Acceso en línea: | https://hdl.handle.net/2445/179897 http://hdl.handle.net/10803/672360 |
| Access Level: | acceso abierto |
| Palabra clave: | Malalties neurodegeneratives Reacció d'oxidació-reducció Metabolisme Lípids Terapèutica Neurodegenerative Diseases Oxidation-reduction reaction Metabolism Lipids Therapeutics |
| Sumario: | [eng] X-linked adrenoleukodystrophy (X-ALD) is a rare neurometabolic disease characterized by the loss of function of the peroxisomal transporter ABCD1, which leads to an accumulation of very long-chain fatty acids (VLCFA), inducing the production of mitochondrial reactive oxygen species. Clinical phenotypes in humans range from adrenal insufficiency to fatal inflammatory cerebral demyelination. Abcd1-null mice (Abcd1- mice) develop late-onset axonal degeneration in the spinal cord and locomotor disability resembling the most common phenotype in humans, adrenomyeloneuropathy (AMN). Oxidative stress and mitochondrial dysfunction are key common features in X- ALD patients as well as in Abcd1- mouse. In this thesis, we sought to explore novel therapeutic targets that would contribute to better understand the pathophysiology of the disease, based on the existing knowledge on these common hallmarks of X-ALD. First, we identified a lipidic imbalance in the X-ALD mouse models (Abcd1- and Abcd1-/Abcd2-/- mice), characterized by the presence of lipid droplet (LD) accumulation, due to overactivation of the mTOR/SREBP-1c axis and its target genes (Chapter I). Next, we studied the effect of pharmacological doses of biotin in redox homeostasis and lipid metabolism in the X- ALD mouse models and fibroblasts derived from healthy subjects and X-ALD patients. In a second study, we investigated the role of E2F1, a transcription factor essential for cell cycle and metabolic homeostasis, in X-ALD pathophysiology. To address this objective, we studied E2F1 expression in the X-ALD mouse models. We found out an increase of E2F1, both at mRNA and protein level, in the spinal cord from Abcd1- and Abcd1-/Abcd2-/- mice. Finally, we explored the therapeutic potential of targeting E2F1 in X-ALD mice. We followed a genetic approach by crossing E2F1-deficient mice with the X-ALD mouse models (Chapter II). Both therapeutic strategies, the pharmacological intervention with high-dose biotin and the genetic inactivation of E2F1, led to an amelioration of i) mitochondrial dysfunction, ii) bioenergetic failure, iii) oxidative damage iv) dysregulated inflammatory profile, and most importantly, v) halted axonal degeneration and behavioural abnormalities in X-ALD mice (Chapters I and II). Collectively, these findings reveal an impairment of the mTOR/SREBP-1c axis that controls lipid homeostasis in X-ALD, as well as point to E2F1 as a candidate for the impaired mitochondrial activity and antioxidant response in X-ALD. Finally, the results of this doctoral thesis indicate that therapies based on correcting lipid accumulation and redox imbalance may be valuable strategies to treat X-ALD and other neurodegenerative disorders which share general dysregulation of lipid metabolism, impaired redox homeostasis, mitochondrial dysfunction, and neuroinflammation among their hallmarks. |
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