Perk Ablation Ameliorates Myelination in S63del-Charcot–Marie–Tooth 1B Neuropathy

• Published in: ASN neuro 2016-03, Vol.8 (2), p.175909141664235
• Main Authors: Musner, Nicolò, Sidoli, Mariapaola, Zambroni, Desireè, Del Carro, Ubaldo, Ungaro, Daniela, D’Antonio, Maurizio, Feltri, Maria L., Wrabetz, Lawrence
• Format: Article
• Language: English
• Subjects: Age Factors; Animals; Animals, Newborn; Cells, Cultured; Charcot-Marie-Tooth Disease - genetics; Charcot-Marie-Tooth Disease - metabolism; Charcot-Marie-Tooth Disease - pathology; Charcot-Marie-Tooth Disease - physiopathology; Coculture Techniques; Disease Models, Animal; eIF-2 Kinase - deficiency; eIF-2 Kinase - genetics; Embryo, Mammalian; Ganglia, Spinal - cytology; Gene Expression Regulation - genetics; Immunoprecipitation; Mice; Mice, Transgenic; Mutation - genetics; Myelin Basic Protein - metabolism; Myelin P0 Protein - genetics; Myelin P0 Protein - metabolism; Neural Conduction - drug effects; Neural Conduction - genetics; Neurons - drug effects; Original; Protein Phosphatase 1 - genetics; Protein Phosphatase 1 - metabolism; Sciatic Nerve - metabolism; Sciatic Nerve - pathology
• ISSN: 1759-0914; 1759-0914
• DOI: 10.1177/1759091416642351

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: Perk haploinsufficiency 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, Perk deficiency in other cells may contribute to demyelination in a non–Schwann-cell autonomous manner.