Ablation of Perk in Schwann Cells Improves Myelination in the S63del Charcot-Marie-Tooth 1B Mouse.
In factory cells, the accumulation of misfolded protein provokes the unfolded protein response (UPR). For example, deletion of serine 63 (S63del) in myelin protein zero (P0) induces P0 accumulation in the endoplasmic reticulum (ER) of Schwann cells and a persistent UPR associated with Charcot-Marie-Tooth 1B (CMT1B) demyelinating peripheral neuropathy in human and mouse. PERK (protein kinase RNA-like ER kinase) is the ER stress sensor that attenuates global translation by phosphorylating eIF2α. Inhibition of the eIF2α holophosphatase GADD34:PP1, increases the phosphorylation of eIF2α in Schwann cells and largely rescues S63del neuropathy. Nonetheless, reducing phosphorylation of eIF2α, by Perk haploinsufficiency, also ameliorates the myelin defects of S63del nerves. This contradictory finding prompted us to investigate whether the beneficial effect of Perk deficiency on myelination could derive from neurons. To test this hypothesis, we generated and compared Schwann cell- and neuron-specific ablation of Perk in S63del nerves. Our data suggest that the detrimental effect of Perk in CMT1B derives primarily from Schwann cells. Furthermore, we show that Perk loss of function in Schwann cells restores myelination without diminishing accumulation of P0 or markers of ER stress, suggesting that Perk may modulate myelination through a pathway independent of the UPR.



In many endoplasmic reticulum (ER) stress-related disorders, activation of the unfolded protein sensor protein kinase RNA-like ER kinase (PERK) kinase is beneficial. Nonetheless, in Charcot-Marie-Tooth 1B neuropathy mice, we show that activation of PERK in Schwann cells, but not in neurons, is detrimental for myelination. PERK may interfere with myelination, independent of its role in ER stress.
Hunter James Kelly Research Institute and.|Departments of Biochemistry and.
Mariapaola
0000-0003-4655-1409
M
Sidoli
Hunter James Kelly Research Institute and.
Nicolò
N
Musner
Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203.
Nicholas
0000-0001-7931-0930
N
Silvestri
Divisions of Neuroscience and.
Daniela
0000-0002-7655-2501
D
Ungaro
Genetics and Cell Biology, San Raffaele Scientific Institute, DIBIT, Milan, Italy 20132, and.
Maurizio
M
D'Antonio
Department of Biology, Center for Cellular Dynamics, Pennsylvania State University, University Park, Pennsylvania 16802.
Douglas R
DR
Cavener
Hunter James Kelly Research Institute and.|Departments of Biochemistry and.|Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203.
M Laura
ML
Feltri
Hunter James Kelly Research Institute and lwrabetz@buffalo.edu.|Departments of Biochemistry and.|Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203.
Lawrence
0000-0003-3360-1032
L
Wrabetz
D000818:Animals; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018993:Myelin P0 Protein / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism* / Q000473:pathology*; D012583:Schwann Cells / Q000378:metabolism* / Q000473:pathology; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000378:metabolism*
D018993:Myelin P0 Protein; D019892:eIF-2 Kinase; C560546:Mpz protein, mouse
Charcot-Marie-Tooth; PERK; Schwann cells; myelin; proteostasis; unfolded protein response