Kleinecke, Sandra

German

Kleinecke, S.

MPG.PuRe

Cellular and subcellular analysis of peripheral neuropathy caused by peroxisomal dysfunction in mice

Fast signal propagation and long-term integrity of myelinated axons rely on precise axo-glial interactions. A role for myelin-associated peroxisomes in facilitating axonal support by glial cells was demonstrated in a mouse model with peroxisome dysfunction specifically in myelinating glia (Cnp-Cre::Pex5flox/flox). This Cnp-Pex5 mouse model was used in the current thesis to analyze the role of peroxisomes in myelin maintenance and Schwann cell (SC)-axon interaction. Here, a critical function of SC lipid metabolism in axonal conduction was proven by ex vivo electrophysiology, showing reduced conduction velocity and decreased amplitudes before behavioral deficits occurred. Unexpectedly, analysis of myelin sheath thickness, compaction, and protein composition excluded dysmyelination as the underlying reason of nerve impairment. Furthermore, the overall number and distribution of myelinated axons was normal. Vesicular accumulations within mutant paranodes could have perturbed paranodal junctions, potentially causing nerve dysfunction. However, axo-glial contact sides at this region were intact. Immunofluorescent staining revealed early-onset redistribution of juxtaparanodal Kv1.1 channels. Nevertheless, the majority of Kv1-clusters was normal in the postnatal phase, and their progressive mislocalization suggested a problem in the maintenance rather than formation. In addition, the Kv1-anchoring protein TAG-1 showed a similar pattern and colocalized with ectopic Kv1.1 ion channels. Within membranes, TAG-1 is associated with gangliosides, a class of glycosphingolipids that were massively perturbed in PEX5 mutant nerves as revealed by lipid mass spectrometry and by (immune-) fluorescent staining. Thus, gangliosides were abundantly present in enlarged vesicles, several of which were identified as lysosomes. Finally, lysosomal marker proteins and enzymatic activities were dramatically increased in mutant nerves, which are typical characteristics of lysosomal storage disorders. Most interestingly, similar pathological features were observed in aged Abcd1-/- mice, a disease model of human adrenomyeloneuropathy, suggesting a common pathomechanism in disorders of peroxisomal β-oxidation. In summary, this work revealed secondary defects of lysosomes as a consequence of peroxisomal dysfunction in vivo and the importance of SC lipid metabolism for normal nerve function, independent of myelin. Since abnormal lipid metabolism is related to several other peripheral neuropathies, this knowledge may provide new therapeutic strategies for other diseases

Georg-August-University Göttingen

English

https://ediss.uni-goettingen.de/bitstream/11858/00-1735-0000-002B-7C99-B/1/PhD%20Thesis%20Sandra%20Kleinecke.pdf

Cellular and subcellular analysis of peripheral neuropathy caused by peroxisomal dysfunction in mice

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MPG.PuRe

Georg-August-University Göttingen

MPG.PuRe