Peroxisomal multifunctional protein-2 deficiency causes neuroinflammation and degeneration of Purkinje cells independent of very long chain fatty acid accumulation

Abstract

Although peroxisome biogenesis and β-oxidation disorders are well known for their neurodevelopmental defects, patients with these disorders are increasingly diagnosed with neurodegenerative pathologies. In order to investigate the cellular mechanisms of neurodegeneration in these patients, we developed a mouse model lacking multifunctional protein 2 (MFP2, also called D-bifunctional protein), a central enzyme of peroxisomal β-oxidation, in all neural cells (Nestin-Mfp2(-/-)) or in oligodendrocytes (Cnp-Mfp2(-/-)) and compared these models with an already established general Mfp2 knockout. Nestin-Mfp2 but not Cnp-Mfp2 knockout mice develop motor disabilities and ataxia, similar to the general mutant. Deterioration of motor performance correlates with the demise of Purkinje cell axons in the cerebellum, which precedes loss of Purkinje cells and cerebellar atrophy. This closely mimics spinocerebellar ataxias of patients affected with mild peroxisome β-oxidation disorders. However, general knockouts have a much shorter life span than Nestin-Mfp2 knockouts which is paralleled by a disparity in activation of the innate immune system. Whereas in general mutants a strong and chronic proinflammatory reaction proceeds throughout the brain, elimination of MFP2 from neural cells results in minor neuroinflammation. Neither the extent of the inflammatory reaction nor the cerebellar degeneration could be correlated with levels of very long chain fatty acids, substrates of peroxisomal β-oxidation. In conclusion, MFP2 has multiple tasks in the adult brain, including the maintenance of Purkinje cells and the prevention of neuroinflammation but this is not mediated by its activity in oligodendrocytes nor by its role in very long chain fatty acid degradation.

Keywords: 17β-hydroxysteroid dehydrogenase type 4 (also called DBP or MFP2); AMN; CNS; Cerebellum; D-bifunctional protein (also called MFP2 and HSD17B4); D-bifunctional protein deficiency; DBP; H&E; HSD17B4; MFP2; Microglia; Mouse model; Multifunctional protein-2; Neuroinflammation; Oligodendrocyte; PBD; Peroxisomal β-oxidation; Purkinje cell; VLCFA; X-ALD; X-linked adrenoleukodystrophy; adrenomyeloneuropathy; cALD; central nervous system; cerebral adrenoleukodystrophy; hematoxylin & eosin; peroxisome biogenesis disorders; very long chain fatty acids.