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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/114447
NRF2 and RIP140 as new therapeutic targets for X-linked adrenoleukodystrophy (X-ALD): Control of redox/metabolic homeostasis and inflammation
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[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, inducing 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 hallmarks of X-ALD. First, we studied the nuclear factor erythroid-derived 2, like 2 (NFE2L2, also known as NRF2), in X-ALD mouse models (Abcd1- and Abcd1-/Abcd2-/- mice) and in fibroblasts derived from healthy subjects and X-ALD patients. Here, we identify that NRF2, the master regulator of endogenous antioxidant response, and its target genes are impaired in X-ALD due to an aberrant activity of the AKT/GSK-3β axis. Moreover, GSK-3β inhibitors reactivated the blunted NRF2-dependent response upon oxidative stress in X-ALD fibroblasts (Chapter I). In a second study, we sought to determine the role of RIP140 (receptor interacting protein 140), a transcriptional coregulator essential for metabolic homeostasis and inflammatory response, in X-ALD pathophysiology. To address this objective we studied RIP140 in Abcd1- mouse, organotypic spinal cord slice cultures (OSCSC) from mice and normal appearing white matter (NAWM) from healthy subjects and cerebral X-ALD patients. We found out a redox-dependent increase of RIP140 in the spinal cord and OSCSC from Abcd1- mice, as well as an induction of RIP140 in the NAWM of childhood cerebral ALD (ccALD) patients (Chapter II). Finally, we explored the therapeutic potential of targeting NRF2 and RIP140, independently, in X-ALD mice (Abcd1- and Abcd1-/Abcd2-/- mice). Regarding NRF2, we followed a pharmacologic approach, by treating Abcd1- and Abcd1-/Abcd2-/- mice with dimethyl fumarate, an FDA-approved NRF2 activator (Chapter I). In the case of RIP140, we followed a genetic approach, by crossing RIP140-deficient mice with X-ALD mouse models (Chapter II). In both cases, the therapeutic intervention led to an amelioration of i) mitochondrial dysfunction, ii) bioenergetic failure, iii) oxidative damage and iv) dysregulated inflammatory profile, and most importantly, halted axonal degeneration and behavioural abnormalities in X-ALD mice (Chapters I and II). Collectively, these findings reveal an impairment of the AKT/GSK-3β/NRF2 axis that controls endogenous response against oxidative stress, as well as point to RIP140 as a candidate for the impaired mitochondrial biogenesis and induction of proinflammatory response in X-ALD. Finally, the results of this doctoral thesis indicate that therapies based on NRF2 activation and RIP140 inhibition may be valuable strategies to treat X-ALD and other neurodegenerative disorders which share impaired redox homeostasis, mitochondrial dysfunction and neuroinflammation among their hallmarks.
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RANEA ROBLES, Pablo. NRF2 and RIP140 as new therapeutic targets for X-linked adrenoleukodystrophy (X-ALD): Control of redox/metabolic homeostasis and inflammation. [consulta: 11 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/114447]