title: Tuning PAK Activity to Rescue Abnormal Myelin Permeability in HNPP.
abstract: Schwann cells in the peripheral nervous systems extend their membranes to wrap axons concentrically and form the insulating sheath, called myelin. The spaces between layers of myelin are sealed by myelin junctions. This tight insulation enables rapid conduction of electric impulses (action potentials) through axons. Demyelination (stripping off the insulating sheath) has been widely regarded as one of the most important mechanisms altering the action potential propagation in many neurological diseases. However, the effective nerve conduction is also thought to require a proper myelin seal through myelin junctions such as tight junctions and adherens junctions. In the present study, we have demonstrated the disruption of myelin junctions in a mouse model (Pmp22+/-) of hereditary neuropathy with liability to pressure palsies (HNPP) with heterozygous deletion of Pmp22 gene. We observed a robust increase of F-actin in Pmp22+/- nerve regions where myelin junctions were disrupted, leading to increased myelin permeability. These abnormalities were present long before segmental demyelination at the late phase of Pmp22+/- mice. Moreover, the increase of F-actin levels correlated with an enhanced activity of p21-activated kinase (PAK1), a molecule known to regulate actin polymerization. Pharmacological inhibition of PAK normalized levels of F-actin, and completely prevented the progression of the myelin junction disruption and nerve conduction failure in Pmp22+/- mice. Our findings explain how abnormal myelin permeability is caused in HNPP, leading to impaired action potential propagation in the absence of demyelination. We call it "functional demyelination", a novel mechanism upstream to the actual stripping of myelin that is relevant to many demyelinating diseases. This observation also provides a potential therapeutic approach for HNPP.
authors: Department of Neurology, Center for Human Genetics Research, Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors: Bo
authors: B
authors: Hu
authors: Department of Neurology, Center for Human Genetics Research, Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors: Sezgi
authors: 0000-0002-6449-4164
authors: S
authors: Arpag
authors: Department of Anatomy and Cell Biology, Wayne State University, Detroit, Michigan, United States of America.
authors: Xuebao
authors: X
authors: Zhang
authors: Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), GÖttingen, Germany.
authors: Wiebke
authors: W
authors: Möbius
authors: Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), GÖttingen, Germany.
authors: Hauke
authors: H
authors: Werner
authors: National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, California, United States of America.
authors: Gina
authors: G
authors: Sosinsky
authors: National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, California, United States of America.
authors: Mark
authors: M
authors: Ellisman
authors: Department of Neurology, Center for Human Genetics Research, Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors: Yang
authors: Y
authors: Zhang
authors: Department of Neurology, Center for Human Genetics Research, Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors: Audra
authors: A
authors: Hamilton
authors: Cancer Biology, Fox Chase Cancer Center, Philadelphia, United States of America.
authors: Jonathan
authors: J
authors: Chernoff
authors: Department of Neurology, Center for Human Genetics Research, Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.|Tennessee Valley Healthcare System, Nashville, Tennessee, United States of America.
authors: Jun
authors: J
authors: Li
mesh_terms: D000199:Actins / Q000378:metabolism; D000200:Action Potentials; D000818:Animals; D001176:Arthrogryposis / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D017353:Gene Deletion; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics / Q000378:metabolism*; D006579:Heterozygote; D007365:Intercellular Junctions / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009185:Myelin Proteins / Q000235:genetics; D009186:Myelin Sheath / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000199:Actins; D009185:Myelin Proteins; C489545:Pmp22 protein, mouse; D047428:Protein Kinase Inhibitors; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases