Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathy.
Sandra KleineckeSarah RichertLivia de HozBritta BrüggerTheresa KunglEbrahim AsadollahiSusanne QuintesJudith BlanzRhona McGonigalKobra NaseriMichael W SeredaTimo SachsenheimerChristian LüchtenborgWiebke MöbiusHugh WillisonMyriam BaesKlaus-Armin NaveCelia Michèle KassmannPublished in: eLife (2017)
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.
Keyphrases
- peripheral nerve
- single cell
- optic nerve
- spinal cord injury
- mouse model
- electron microscopy
- white matter
- optical coherence tomography
- fatty acid
- endothelial cells
- cell therapy
- poor prognosis
- oxidative stress
- image quality
- neuropathic pain
- metabolic syndrome
- stem cells
- long non coding rna
- magnetic resonance imaging
- adipose tissue
- insulin resistance
- bone mineral density
- postmenopausal women
- skeletal muscle
- magnetic resonance
- contrast enhanced