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.

In vivo labeling of peroxisomes by photoconvertible mEos2 in myelinating glia of mice.

Mutations of several genes encoding peroxisomal proteins have been associated with human diseases. Some of these display specific white matter abnormalities in the brain, although the affected proteins are ubiquitously expressed. To better understand the etiology of peroxisomal myelin diseases, we aimed to label these organelles in vivo and in a cell type specific fashion. We had previously shown that in oligodendrocytes and Schwann cells numerous peroxisomes reside in the cytoplasmic channels of "non-compacted" myelin. These organelles are smaller and biochemically distinct from non-myelin peroxisomes. Targeting peroxisomal functions in various cell types of the brain has demonstrated that oligodendroglial peroxisomes are specifically important for long-term integrity of the CNS. To visualize myelin peroxisomes in intact cells and tissues by live imaging, we have generated a novel line of transgenic mice for the expression of fluorescently tagged peroxisomes specifically in myelinating glia. This was achieved by modifying the gene for a photoconvertible mEos2 with a peroxisomal targeting signal type 1 (PTS1) and generating a fusion gene with the myelin-specific Cnp1 promoter. In the brain of resulting transgenic mice, peroxisomes are selectively labeled in oligodendrocytes. In this novel genetic tool, photoconversion of single peroxisomes from green to red fluorescence can be used to monitor the fate of single organelles and to determine the dynamics of PTS1-mediated protein import in the context of myelin diseases that affect peroxisomal functions.