Perk Ablation Ameliorates Myelination in S63del-Charcot-Marie-Tooth 1B Neuropathy.
In peripheral nerves, P0 glycoprotein accounts for more than 20% of myelin protein content. P0 is synthesized by Schwann cells, processed in the endoplasmic reticulum (ER) and enters the secretory pathway. However, the mutant P0 with S63 deleted (P0S63del) accumulates in the ER lumen and induces a demyelinating neuropathy in Charcot-Marie-Tooth disease type 1B (CMT1B)-S63del mice. Accumulation of P0S63del in the ER triggers a persistent unfolded protein response. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) is an ER stress sensor that phosphorylates eukaryotic initiation factor 2 alpha (eIF2alpha) in order to attenuate protein synthesis. We have shown that increasing phosphophorylated-eIF2alpha (P-eIF2alpha) is a potent therapeutic strategy, improving myelination and motor function in S63del mice. Here, we explore the converse experiment:Perkhaploinsufficiency reduces P-eIF2alpha in S63del nerves as expected, but surprisingly, ameliorates, rather than worsens S63del neuropathy. Motor performance and myelin abnormalities improved in S63del//Perk+/- compared with S63del mice. These data suggest that mechanisms other than protein translation might be involved in CMT1B/S63del neuropathy. In addition,Perkdeficiency in other cells may contribute to demyelination in a non-Schwann-cell autonomous manner.
Hunter James Kelly Research Institute, University at Buffalo, NY, USA.
Nicolò
N
Musner
Hunter James Kelly Research Institute, University at Buffalo, NY, USA Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, NY, USA.
Mariapaola
M
Sidoli
Division of Neuroscience, San Raffaele Scientific Institute, DIBIT, Milan, Italy.
Desireè
D
Zambroni
Division of Neuroscience, San Raffaele Scientific Institute, DIBIT, Milan, Italy.
Ubaldo
U
Del Carro
Division of Neuroscience, San Raffaele Scientific Institute, DIBIT, Milan, Italy.
Daniela
D
Ungaro
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, DIBIT, Milan, Italy.
Maurizio
M
D'Antonio
Hunter James Kelly Research Institute, University at Buffalo, NY, USA Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, NY, USA Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, NY, USA.
Maria L
ML
Feltri
Hunter James Kelly Research Institute, University at Buffalo, NY, USA Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, NY, USA Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, NY, USA lwrabetz@buffalo.edu.
Lawrence
L
Wrabetz
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D018920:Coculture Techniques; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000235:genetics; D047468:Immunoprecipitation; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D004676:Myelin Basic Protein / Q000378:metabolism; D018993:Myelin P0 Protein / Q000235:genetics / Q000378:metabolism; D009431:Neural Conduction / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000187:drug effects; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology; D019892:eIF-2 Kinase / Q000172:deficiency* / Q000235:genetics
D004676:Myelin Basic Protein; D018993:Myelin P0 Protein; D054645:Protein Phosphatase 1; D019892:eIF-2 Kinase; C513256:Ppp1r15a protein, mouse
Charcot–Marie–Tooth; PERK; Schwann cells; myelin; proteostasis; unfolded protein response