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

Verheijden, Simon; Bottelbergs, Astrid; Krysko, Olga; Krysko, Dmitri V.; Beckers, Lien; Munter, Stephanie De; Veldhoven, Paul P. Van; Wyns, Sabine; Kulik, Wim; Nave, Klaus‐Armin; Ramer, Matt S.; Carmeliet, Peter; Kassmann, Celia M.; Baes, Myriam

doi:10.1016/j.nbd.2013.06.006

Cited by 45 publications

(97 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, we found that Cnp-Cre::Hsd17b4 flox/flox mice (referred to as MFP2 conditional knockout mice in the following), which specifically lack peroxisomal β-oxidation (Verheijden et al, 2013), share the key features of this novel phenotype, including ectopic internodal K v 1.1 clusters (Figure 4—figure supplement 1a–e), confirming the important role for glial lipid metabolism in maintaining axonal membrane composition, and function.…”

Section: Resultsmentioning

confidence: 61%

“…A more severe impairment of peroxisomes is caused by lack of the Hsd17b4 gene (also called multifunctional protein 2; Mfp2 gene) that encodes a central enzyme of peroxisomal β-oxidation. In MFP2-deficient cells, the β-oxidation of virtually all peroxisome-specific substrates, including VLCFA, is inhibited (Verheijden et al, 2013). A complete disruption of the organelle is observed in the absence of peroxisome biogenesis factor peroxin 5 (PEX5).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathy

Kleinecke

Richert

Hoz

et al. 2017

eLife

Self Cite

View full text Add to dashboard Cite

Impairment of peripheral nerve function is frequent in neurometabolic diseases, but mechanistically not well understood. Here, we report a novel disease mechanism and the finding that glial lipid metabolism is critical for axon function, independent of myelin itself. Surprisingly, nerves of Schwann cell-specific Pex5 mutant mice were unaltered regarding axon numbers, axonal calibers, and myelin sheath thickness by electron microscopy. In search for a molecular mechanism, we revealed enhanced abundance and internodal expression of axonal membrane proteins normally restricted to juxtaparanodal lipid-rafts. Gangliosides were altered and enriched within an expanded lysosomal compartment of paranodal loops. We revealed the same pathological features in a mouse model of human Adrenomyeloneuropathy, preceding disease-onset by one year. Thus, peroxisomal dysfunction causes secondary failure of local lysosomes, thereby impairing the turnover of gangliosides in myelin. This reveals a new aspect of axon-glia interactions, with Schwann cell lipid metabolism regulating the anchorage of juxtaparanodal Kv1-channels.DOI: http://dx.doi.org/10.7554/eLife.23332.001

show abstract

Section: Resultsmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathy

Kleinecke

Richert

Hoz

et al. 2017

eLife

Self Cite

View full text Add to dashboard Cite

show abstract

“…Very long-chain fatty acids participate in a wide variety of physiological functions, including skin barrier formation 14 and peroxisome β-oxidation, which is known to be involved in several neurodevelopmental disorders. 19 After differentiation of the keratinocytes, different layers of the epidermis are developed, including the stratum corneum. 20 This outermost layer of the epidermis acts as a transepidermal barrier that prevents dehydration.…”

Section: Discussionmentioning

confidence: 99%

Expanding the Clinical Phenotype Associated WithELOVL4Mutation

et al. 2014

View full text Add to dashboard Cite

IMPORTANCE The autosomal dominant spinocerebellar ataxias (SCAs) are a complex group of neurodegenerative disorders with significant genetic heterogeneity. Despite the identification of 20 SCA genes, the cause of the disorder in a significant proportion of families with SCA remains unexplained. In 1972, a French-Canadian family segregating a combination of SCA and erythrokeratodermia variabilis (EKV) in an autosomal dominant fashion was described.OBJECTIVE To map and identify the causative gene in this large family with SCA and EKV using a combination of linkage analysis and whole-exome sequencing. DESIGN, SETTING, AND PARTICIPANTSA total of 32 individuals from the family have undergone complete neurologic and dermatologic examinations.MAIN OUTCOMES AND MEASURES Mutations in ELOVL4 have been reported in families with macular degeneration. Recently, homozygous mutations were found in patients with ichthyosis, spastic paraplegia, and severe neurodevelopmental defects. In the present study, we report on a heterozygote mutation in ELOVL4 in affected individuals from the family with SCA and EKV. The mutation segregates with a milder phenotype consisting of early-onset patches of erythema and hyperkeratosis, as well as SCA manifesting in the fourth or fifth decade of life. RESULTSWe describe the mapping and the identification of a c.504G>C transversion in ELOVL4 resulting in the p.L168F substitution. We also provide clinical characterization of the phenotypes in 19 mutation carriers. CONCLUSIONS AND RELEVANCEWe report, to our knowledge, the first mutation in ELOVL4 that is associated with SCA and EKV. This gene encodes a member of the elongase family, which is responsible for the elongation of very long-chain fatty acids (at least 26 carbons). These fatty acids participate in a wide variety of physiological functions, including skin barrier formation and peroxisome β-oxidation. Overall, these results provide additional insight into the pathogenesis of these complex neurodegenerative disorders.

show abstract

“…It is possible that a pro-inflammatory milieu is caused by the accumulation of eicosanoids (prostaglandins and leukotrienes) that are normally degraded by peroxisomal β-oxidation (Kassmann and Nave, 2008). However, the specific blockage of only peroxisomal β-oxidation in oligodendrocytes (Cnp1-Cre*Mfp2 flox/flox ) does not cause an equivalent degree of inflammatory demyelination (Verheijden et al, 2013).…”

Section: Neuroinflammation Of White Matter In Mouse Models Of Peroxismentioning

confidence: 99%

Molecular triggers of neuroinflammation in mouse models of demyelinating diseases

Barrette

Nave

Edgar³

2013

Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Myelinating cells wrap axons with multi-layered myelin sheaths for rapid impulse propagation. Dysfunctions of oligodendrocytes or Schwann cells are often associated with neuroinflammation, as observed in animal models of leukodystrophies and peripheral neuropathies, respectively. The neuroinflammatory response modulates the pathological changes, including demyelination and axonal injury, but also remyelination and repair. Here we discuss different immune mechanisms as well as factors released or exposed by myelinating glia in disease conditions. The spectrum of inflammatory mediators varies with different myelin disorders and has a major impact on the beneficial or detrimental role of immune cells in keeping nervous system integrity.

show abstract

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

Cited by 45 publications

References 49 publications

Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathy

Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathy

Expanding the Clinical Phenotype Associated WithELOVL4Mutation

Molecular triggers of neuroinflammation in mouse models of demyelinating diseases

Contact Info

Product

Resources

About