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

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.

Oligodendroglial impact on axonal function and survival - a hypothesis.

PURPOSE OF REVIEW: Although multiple sclerosis is considered the prototype of a primary autoimmune disease in the central nervous system, there is emerging evidence that primary oligodendrocyte dysfunctions can suffice to trigger a secondary immune response in the nervous system. This short review focuses on the possible primary role of oligodendrocytes in axon loss and inflammatory demyelination. RECENT FINDINGS: The analysis of natural and engineered mouse mutants has provided unexpected insight into oligodendrocyte function beyond that of axonal myelination for rapid impulse propagation. Specifically, mutations in some genes thought to be required for myelin assembly revealed an additional role of oligodendrocytes in supporting long-term axonal function and survival. Other mutations have been reported that cause both central nervous system demyelination and neuroinflammation, with pathological features known from human leukodystrophy patients. In human multiple sclerosis, demyelination leads invariably to axon loss, but the underling pathomechanisms may not be restricted to that of a primary immune-mediated disorder. SUMMARY: Collectively, experimental and pathological findings point to a primary role of myelinating glia in long-term axonal support and suggest that defects of lipid metabolism in oligodendrocytes contribute to inflammatory myelin diseases.