Mutations in human PMP22 cause the most common forms of inherited peripheral nerve diseases, which include hereditary neuropathy with liability to pressure palsies (HNPP) with heterozygous deletion of PMP22. Patients with HNPP presents with focal sensory loss and muscle weakness that are related to the conduction block. We have discovered that PMP22 deficiency impairs action potential propagation in the absence of segmental demyelination. This conduction defect is likely resulted from abnormally increased permeability of myelin through disruption of myelin junctions. In the present study, we will investigate how junction complexes are disrupted through their abnormal maintenance in PMP22 deficient nerves.
Aim 1 : Test the hypothesis that PMP22 deficiency increases actin polymerization at myelin junctions, leading to removal of myelin junction protein complexes. Our preliminary study has demonstrated a remarkable increase of F-actin overlaps with the areas that show disruption of junction protein complexes. We will utilize genetically labeled F-actin mouse model to track dynamics of F-actin formation. We will further test how PMP22 deficiency activates the actin polymerization.
Aim 2 : Removal of p21-activated kinase (PAK1) reverses the increase of F-actin in PMP22 deficient nerves, and thereby prevents myelin junction complexes from being disrupted. Our preliminary results show an abnormal increase of PAK1 activity in Pmp22+/- nerves. Ablation of Pak1 in Pmp22+/- mice reverses abnormal myelin permeability. We will use the double knockout mice (Pmp22+/- /Pak1-/-) to determine whether removal of PAK1 suppresses the formation of F-actin, and dislocation of junction complexes in HNPP mouse model. Moreover, utilizing our newly produced transgenic mouse expressing PAK-inhibiting peptides under the control of inducible Schwann cell-specific cre, we will determine the temporal requirement in rescuing junction abnormalities via PAK inhibition.
Aim 3 : Systemic administration of PAK1 inhibitor reverses the phenotype in the HNPP mouse model. A successful reversal of abnormal myelin permeability by deletion of Pak1 in Pmp22+/- mice strongly justifies a therapeutic trial in Pmp22+/- mice using PAK1 inhibitors. Taken together, these three aims will further substantiate the pathogenic roles of myelin junction disruption and abnormal actin polymerization in HNPP. We are optimistic that a therapy will likely be developed through this study. Because myelin junctions are essential complexes that seal myelin, results derived from this study may have broad applications in other myelin diseases.

Public Health Relevance

Conduction block (CB), a failure of propagation of electrical signal along nerve fibers, causes disabilities in a variety of neurological disorders. Patients wit hereditary neuropathy with liability to pressure palsies present with frequent focal weakness and sensory loss, which are likely caused by CB. Our study investigates molecular mechanisms responsible for the CB using HNPP and its animal model.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS066927-07
Application #
9031163
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Nuckolls, Glen H
Project Start
2010-03-15
Project End
2016-03-02
Budget Start
2016-03-01
Budget End
2016-03-02
Support Year
7
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Neurology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37240
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Moiseev, Daniel; Hu, Bo; Li, Jun (2018) Morphometric analysis of peripheral myelinated nerve fibers through deep learning. J Peripher Nerv Syst :
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Mittendorf, Kathleen F; Marinko, Justin T; Hampton, Cheri M et al. (2017) Peripheral myelin protein 22 alters membrane architecture. Sci Adv 3:e1700220
Hu, Bo; Arpag, Sezgi; Zuchner, Stephan et al. (2016) A novel missense mutation of CMT2P alters transcription machinery. Ann Neurol 80:834-845
Kramer, Mark; Ly, Amy; Li, Jun (2016) Phenotype HNPP (Hereditary Neuropathy With Liability to Pressure Palsies) Induced by Medical Procedures. Am J Orthop (Belle Mead NJ) 45:E27-8
Yang, Yi; Gu, Li-Qiang; Burnette, William B et al. (2016) N98S mutation in NEFL gene is dominantly inherited with a phenotype of polyneuropathy and cerebellar atrophy. J Neurol Sci 365:46-7
Hu, Bo; Arpag, Sezgi; Zhang, Xuebao et al. (2016) Tuning PAK Activity to Rescue Abnormal Myelin Permeability in HNPP. PLoS Genet 12:e1006290
Zou, Jianlong; Hu, Bo; Arpag, Sezgi et al. (2015) Reactivation of Lysosomal Ca2+ Efflux Rescues Abnormal Lysosomal Storage in FIG4-Deficient Cells. J Neurosci 35:6801-12

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