Peroxisomal Disorders: A Review on Cerebellar Pathologies

Abstract

Peroxisomes are organelles with diverse metabolic tasks including essential roles in lipid metabolism. They are of utmost importance for the normal functioning of the nervous system as most peroxisomal disorders are accompanied with neurological symptoms. Remarkably, the cerebellum exquisitely depends on intact peroxisomal function both during development and adulthood. In this review, we cover all aspects of cerebellar pathology that were reported in peroxisome biogenesis disorders and in diseases caused by dysfunction of the peroxisomal α-oxidation, β-oxidation or ether lipid synthesis pathways. We also discuss the phenotypes of mouse models in which cerebellar pathologies were recapitulated and search for connections with the metabolic abnormalities. It becomes increasingly clear that besides the most severe forms of peroxisome dysfunction that are associated with developmental cerebellar defects, milder impairments can give rise to ataxia later in life.

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

“…The fact that PC axonal abnormalities preceded neurodegeneration in L7-Mfp2 2/2 mice is compatible with a dying-back neuropathy whereby the cells start degenerating at the synapse and provoke retrograde PC death (5) (Figure 9). It is striking that axonal spheroids were also the earliest histological anomalies in cerebella of Nestin-Mfp2 2/2 mice (8). While previously we mainly put our attention on myelin and oligodendrocyte abnormalities as factors likely causing swellings on PC axons in MFP2 deficiency (8,40), we here show that MFP2 in PCs itself is crucial to prevent their axons from degenerating.…”

“…In PC degeneration and Lurcher mutant mice, for example, virtually all PCs degenerated while they only displayed mild motor signs . The fact that the early‐onset motor phenotype of Mfp2 −/− and Nestin‐Mfp2 −/− mice is not recapitulated in the L7‐Mfp2 −/− model strengthens the necessity of an intact peroxisomal β‐oxidation in structures within the neural circuit innervating the PCs and/or in the neighboring glial cells. This once again proves the importance of an intact peroxisomal metabolism during brain development.…”

“…While we recently demonstrated the primordial role of the pivotal peroxisomal β‐oxidation enzyme MFP2 for the functioning, morphology and innervation of cerebellar PCs , the question remained what cell types are at the origin of cerebellar degeneration in MFP2 deficiency. In this study, we explored the cell autonomous role of peroxisomal β‐oxidation in PCs by generating a PC specific knockout mouse model of MFP2, L7‐Mfp2 −/− .…”

Tauroursodeoxycholic bile acid arrests axonal degeneration by inhibiting the unfolded protein response in X-linked adrenoleukodystrophy

“…The loss or malfunction of peroxisomes is the cause of more than 20 fatal inherited conditions, which are classified into two main groups: (i) peroxisome biogenesis (PBD) and (ii) single peroxisomal enzyme deficiencies. Mutations in peroxisomal proteins that are essential for biogenesis and membrane protein import (called peroxins or PEX genes) invariably lead to PBD, with Zellweger syndrome as the most severe manifestation [3, 16, 83, 102, 103], (see also http://www.peroxisomedb.org). …”

Plasmalogen homeostasis – regulation of plasmalogen biosynthesis and its physiological consequence in mammals

“…Several physiological roles of plasmalogens are suggested from analyses of defects in plasmalogen-deficient or -reduced cells [30, [65][66][67][68][69][70][71] and animals [19,61,[72][73][74][75][76][77][78]. Recent reviews on the functions of plasmalogens are also recommended [2,5,62, [79][80][81][82].…”