Mechanisms of neurodegeneration caused by peroxisomal beta-oxidation deficiency.

The central nervous system is among the tissues most enriched in lipids and lipid abnormalities are increasingly considered to contribute to the pathogenesis of rare and common neurodegenerative disorders. Peroxisomes, the latest discovered cell organelles, play an essential role in lipid homeostasis but their precise contributions were not elucidated yet. Peroxisomal disorders are inherited diseases characterized by developmental and/or degenerative central nervous system pathologies. In the present project we aim to decipher why peroxisomal β-oxidation is necessary for the maintenance of brain integrity. We previously showed that both neuroinflammation and motor problems develop in Mfp2 knockout mice that lack a crucial enzyme of peroxisomal β-oxidation. We will investigate the mechanisms causing ataxia and Purkinje cell degeneration, by using different cell type selective Mfp2 knockout mice and immunohistochemical and gene expression analysis. Bone marrow transplantation and hematopoietic stem cell gene therapy will be applied on Mfp2 knockout mice to rescue them from inflammatory degeneration. This mimicks the therapy of X-linked adrenoleukodystrophy patients the mechanisms of which is not understood despite its lifesaving success. Finally, in order to explore the origins of pathology, lipid abnormalities will be examined by imaging mass spectrometry, a novel technique that allows to detect altered lipid composition in brain regions, and by other approaches.