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 language | English (US) |
|---|---|
| Pages (from-to) | 11350-11361 |
| Number of pages | 12 |
| Journal | Journal of Neuroscience |
| Volume | 36 |
| Issue number | 44 |
| DOIs | |
| State | Published - Nov 2 2016 |
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All Science Journal Classification (ASJC) codes
- Neuroscience(all)
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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 journal › Article
TY - JOUR
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
PY - 2016/11/2
Y1 - 2016/11/2
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84994453244&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84994453244&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.1637-16.2016
DO - 10.1523/JNEUROSCI.1637-16.2016
M3 - Article
C2 - 27807175
AN - SCOPUS:84994453244
VL - 36
SP - 11350
EP - 11361
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 44
ER -