Tuning PAK Activity to Rescue Abnormal Myelin Permeability in HNPP
Fig 1
Schematic illustration of myelin junction disruption.
(A) Mechanism of functional demyelination (modified from Guo et al, Ann Neurol 2014): Myelin junctions in Pmp22+/+ nerve are in non-compact myelin regions, including paranodes, incisures and mesaxons. These junctions seal the spaces between myelin lamina. A Pmp22+/- nerve fiber is depicted and develops a tomaculae in the left paranode extending into juxtaparanode and internode, but there is no segmental demyelination. However, junction protein complexes are disrupted or disappeared in the non-compact myelin. These junction proteins may be found in aberrant locations, including perinuclear areas or tomaculous myelin. Abnormal junctions in Pmp22+/- nerves increase myelin permeability (or increase of capacitance). (B) Molecular architecture of junction protein complex: Transmembrane proteins establish "trans-adhesion" between opposing membranes. Through adaptor proteins, such as ZO1/2 or catenins, these junction protein complexes are stabilized by sub-membrane actin networks. Alteration of the actin network has been shown to disassemble junctions in epithelial cell models [29, 30].