Objective:

Background:

PMP22 is a key myelin protein in the peripheral nervous system (PNS), located in lipid-enriched compact myelin. Heterozygous deletion of PMP22 (Pmp22^+/-) leads to hereditary neuropathy with liability to pressure palsies (HNPP), which is pathologically characterized by tomacula. PMP22 has multiple lipid-interactive motifs, thus we hypothesize that the reduction of PMP22 in HNPP alters myelin lipid composition. Moreover, our recent study has identified PAK2 as a promyelinating factor whose activities are regulated by myelin lipids (Hu et al, Brain 2024). Therefore, PMP22 deficiency may affect PAK2 activity by altering myelin lipid levels.

Design/Methods:

We used liquid chromatography-mass spectrometry to profile myelin lipids and immunoblotting to assess PAK2 activity in the sciatic nerves of 3-month-old wild-type (Pmp22^+/+) and Pmp22^+/- mice, an HNPP mouse model (3 males and 3 females per genotype).

Results:

Lipidomics revealed a significant increase in specific myelin lipids including C24:1 sphingomyelin, sphingosine, dihydrosphingosine, C18:0:20:4-diacylglycerol, and various ceramide-1-phosphates in Pmp22^+/- nerves, compared to those in Pmp22^+/+ nerves (P<0.05). Sphingosine inhibits PAK2 activity in the soluble fraction of Schwan cells while enhancing PAK2 activity in the insoluble fraction. The remaining lipids on PAK2 have yet to be tested. Western blot analysis indicated a significant reduction in phosphorylated PAK2 at Ser20 in Pmp22^+/- nerves, compared with those in Pmp22^+/+ nerves (Ratio of Ser20/t PAK2: Pmp22^+/+ 0.61±0.25 versus Pmp22^+/- 0.19±0.10, P<0.0001).

Conclusions:

This study shows alterations in myelin lipid profiles in HNPP. These altered myelin lipids may affect the promyelinating factor PAK2 activity. Taken together, these data reveal a novel lipid-protein interaction signaling in regulating myelination. The application of myelin lipids on PAK2 activation offers a new avenue in developing therapies against HNPP.