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

Abstract

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

PIP4K2A regulates intracellular cholesterol transport through modulating PI(4,5)P2 homeostasis

“…It is also known that peroxisomal disorders are accompanied with cholesterol accumulation in lysosomes (8,9), demonstrating that peroxisome plays an important role in cholesterol transport from lysosome. Although the regulation of PIP4K2A is not well characterized, there are some clues suggesting PIP4K2A may be involved in LSD in previous studies.…”

“…Depletion of peroxisomal PI(4,5)P 2 results in cholesterol accumulation in lysosomes (8). Lysosome-peroxisome association is also observed in mouse neurons (9). Peroxisomal dysfunction caused expanded lysosomes likely due to impairment of the organelle contacts (9).…”

“…Lysosome-peroxisome association is also observed in mouse neurons (9). Peroxisomal dysfunction caused expanded lysosomes likely due to impairment of the organelle contacts (9). Cells were washed and fixed as indicated before (12).…”

X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies

“…In this mouse, axonopathy progression was halted and biochemical markers of oxidation and ER stress were ameliorated by antioxidant compound and TUCDA bile acid therapies. (Fourcade, Lopez-Erauskin, Ruiz, Ferrer, & Pujol, 2014;Launay et al, 2017;Lopez-Erauskin et al, 2011) In the peripheral nerves of the Abcd1 mouse, Kleinecke demonstrated lysosomal storage and increased VLCFA in gangliosides of lipid rafts causing altered axonal Kv1 channels in Schwann cells leading to peripheral neuropathy which was age dependent (Islinger et al, 2018;Kleinecke et al, 2017).…”

From peroxisomal disorders to common neurodegenerative diseases – the role of ether phospholipids in the nervous system

“…In Schwann cells, the defect in ether lipid biosynthesis was demonstrated to impair the recruitment of AKT to the plasma membrane thereby inhibiting its proper phosphorylation, which in turn causes aberrant phosphorylation and overt activation of the downstream kinase glycogen synthase kinase (GSK) 3β and finally impaired myelin formation and maintenance . However, a recent study of mice with Schwann cell‐selective KO of Pex5 did not reveal such abnormalities in myelination suggesting that the inherent defect in Schwann cells is only one aspect of the myelination problem and that also interaction with other compartments (e.g., axons) with additional disturbances is involved in mice with global ether lipid deficiency. Another study found decreased phosphorylation of both AKT and ERK phosphorylation after injection of lentiviral shRNAs against the Gnpat mRNA into the cerebral cortex of mice ; while exogenous supplementation with plasmalogens in cultured neuronal cells was suggested to enhance AKT and ERK phosphorylation via the induction of G protein‐coupled receptors .…”