Ablation of Perk in schwann cells improves myelination in the S63del charcot-marie-tooth 1B mouse

Mariapaola Sidoli, Nicolò Musner, Nicholas Silvestri, Daniela Ungaro, Maurizio D’Antonio, Douglas R. Cavener, M. Laura Feltri, Lawrence Wrabetz

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)11350-11361
Number of pages12
JournalJournal of Neuroscience
Volume36
Issue number44
DOIs
StatePublished - Nov 2 2016

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Schwann Cells
Tooth
Unfolded Protein Response
Endoplasmic Reticulum Stress
Endoplasmic Reticulum
Myelin P0 Protein
Phosphorylation
Neurons
Haploinsufficiency
Protein Unfolding
Peripheral Nervous System Diseases
Myelin Sheath
Protein Kinases
Serine
Phosphotransferases
RNA

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Sidoli, Mariapaola ; Musner, Nicolò ; Silvestri, Nicholas ; Ungaro, Daniela ; D’Antonio, Maurizio ; Cavener, Douglas R. ; Laura Feltri, M. ; Wrabetz, Lawrence. / Ablation of Perk in schwann cells improves myelination in the S63del charcot-marie-tooth 1B mouse. In: Journal of Neuroscience. 2016 ; Vol. 36, No. 44. pp. 11350-11361.
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abstract = "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.",
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Sidoli, M, Musner, N, Silvestri, N, Ungaro, D, D’Antonio, M, Cavener, DR, Laura Feltri, M & Wrabetz, L 2016, 'Ablation of Perk in schwann cells improves myelination in the S63del charcot-marie-tooth 1B mouse', Journal of Neuroscience, vol. 36, no. 44, pp. 11350-11361. https://doi.org/10.1523/JNEUROSCI.1637-16.2016

Ablation of Perk in schwann cells improves myelination in the S63del charcot-marie-tooth 1B mouse. / Sidoli, Mariapaola; Musner, Nicolò; Silvestri, Nicholas; Ungaro, Daniela; D’Antonio, Maurizio; Cavener, Douglas R.; Laura Feltri, M.; Wrabetz, Lawrence.

In: Journal of Neuroscience, Vol. 36, No. 44, 02.11.2016, p. 11350-11361.

Research output: Contribution to journalArticle

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T1 - Ablation of Perk in schwann cells improves myelination in the S63del charcot-marie-tooth 1B mouse

AU - Sidoli, Mariapaola

AU - Musner, Nicolò

AU - Silvestri, Nicholas

AU - Ungaro, Daniela

AU - D’Antonio, Maurizio

AU - Cavener, Douglas R.

AU - Laura Feltri, M.

AU - Wrabetz, Lawrence

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N2 - 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.

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