Autonomous Purkinje cell axonal dystrophy causes ataxia in peroxisomal multifunctional protein‐2 deficiency

Abstract

Peroxisomes play a crucial role in normal neurodevelopment and in the maintenance of the adult brain. This depends largely on intact peroxisomal β-oxidation given the similarities in pathologies between peroxisome biogenesis disorders and deficiency of multifunctional protein-2 (MFP2), the central enzyme of this pathway. Recently, adult patients diagnosed with cerebellar ataxia were shown to have mild mutations in the MFP2 gene, hydroxy-steroid dehydrogenase (17 beta) type 4 (HSD17B4). Cerebellar atrophy also develops in MFP2 deficient mice but the cellular origin of the degeneration is unexplored. In order to investigate whether peroxisomal β-oxidation is essential within Purkinje cells, the sole output neurons of the cerebellum, we generated and characterized a mouse model with Purkinje cell selective deletion of the MFP2 gene. We show that selective loss of MFP2 from mature cerebellar Purkinje neurons causes a late-onset motor phenotype and progressive Purkinje cell degeneration, thereby mimicking ataxia and cerebellar deterioration in patients with mild HSD17B4 mutations. We demonstrate that swellings on Purkinje cell axons coincide with ataxic behavior and precede neurodegeneration. Loss of Purkinje cells occurs in a characteristic banded pattern, proceeds in an anterior to posterior fashion and is accompanied by progressive astro- and microgliosis. These data prove that the peroxisomal β-oxidation pathway is required within Purkinje neurons to maintain their axonal integrity, independent of glial dysfunction.

Microglia lacking a peroxisomal β-oxidation enzyme chronically alter their inflammatory profile without evoking neuronal and behavioral deficits

“…Therefore, we used both Cre -positive and Cre -negative mice as control animals. Because reliable antibodies for immunohistochemical detection of MFP2 are not available [30], we confirmed the recombination of Mfp2 in microglia of Cx3cr1-Mfp2 −/− mice using transcript analysis on MACS-isolated microglia. The selectivity of Mfp2 recombination was further confirmed by the normal expression of MFP2 in the non-microglia fraction and by the fact that the activity of MFP2 was not significantly reduced in whole brain homogenates (Additional file 2: Figure S2).…”

The peroxisome: an update on mysteries 2.0

“…It remained to be clarified, if the individual β-oxidation in the main neuronal cell types also contributes to the brain pathology. To this end, the Baes group established a nestin–MFP2 −/− strain ablating peroxisomal β-oxidation in all neural cell types (nestin–MFP2 −/− ), an oligodendrocyte-specific MFP2 deletion (Cnp–MFP2 −/− ) and a Purkinje cell-specific deletion (L7–MFP2 −/− ) strain (Verheijden et al 2013 ; De Munter et al 2018 ). The nestin–MFP2 −/− mouse showed the most severe pathology establishing a locomotor phenotype comparable to the constitutive MFP2 knockout.…”

“…In contrast, such compensation is not possible for the Purkinje cell-specific deletion in the correspondent L7–MFP2 −/− mice. This strain developed symptoms of ataxia already at the age of 6 months and showed a significant decline in Purkinje cell numbers at later stages (De Munter et al 2018 ). According to these findings, the role of peroxisomal metabolism in the CNS appears to be more complex than previously anticipated.…”

Miro—Working beyond Mitochondria and Microtubules

“…Microtubule-dependent peroxisome movement is found to be impaired in cells with spastin gene ( SPAST ) mutations from patients with Hereditary Spastic Paraplegia [ 35 ]. Deficiency in the peroxisome fatty acid β-oxidation multifunctional protein-2 (MFP2) causes cerebellar ataxia resulting from Purkinje cell axonal dystrophy [ 36 ]. The above non-exhaustive list of examples illustrates the importance in understanding Miro activity and its potential dysfunction that may lead to combinatorial mitochondrial and peroxisome defects in diseases.…”