RGD Reference Report - The unfolded protein response is a major mechanism by which LRP1 regulates Schwann cell survival after injury. - Rat Genome Database

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The unfolded protein response is a major mechanism by which LRP1 regulates Schwann cell survival after injury.

Authors: Mantuano, E  Henry, K  Yamauchi, T  Hiramatsu, N  Yamauchi, K  Orita, S  Takahashi, K  Lin, JH  Gonias, SL  Campana, WM 
Citation: Mantuano E, etal., J Neurosci. 2011 Sep 21;31(38):13376-85.
RGD ID: 5685664
Pubmed: PMID:21940431   (View Abstract at PubMed)
PMCID: PMC3188465   (View Article at PubMed Central)
DOI: DOI:10.1523/JNEUROSCI.2850-11.2011   (Journal Full-text)

In peripheral nerve injury, Schwann cells (SCs) must survive to exert a continuing and essential role in successful nerve regeneration. Herein, we show that peripheral nerve injury is associated with activation of endoplasmic reticulum (ER) stress and the adaptive unfolded protein response (UPR). The UPR culminates in expression of C/EBP homology protein (CHOP), a proapoptotic transcription factor in SCs, unless counteracted by LDL receptor-related protein-1 (LRP1), which serves as a major activator of phosphatidylinositol 3-kinase (PI3K). Sciatic nerve crush injury in rats induced expression of the ER chaperone GRP78/BIP, reflecting an early, corrective phase of the UPR. However, when LRP1 signaling was inhibited with receptor-associated protein, PI3K activity was decreased and CHOP protein expression increased, particularly in myelinating SCs. In cultured SCs, the PKR-like ER kinase target eIF2alpha was phosphorylated and CHOP was induced by (1) inhibiting PI3K, (2) treating the cells with tumor necrosis factor-alpha (TNF-alpha), or (3) genetic silencing of LRP1. CHOP gene deletion in SCs decreased cell death in response to TNF-alpha. Furthermore, the effects of TNF-alpha on phosphorylated eIF2alpha, CHOP, and SC death were blocked by adding LRP1 ligands that augment LRP1-dependent cell signaling to PI3K. Collectively, our results support a model in which UPR-activated signaling pathways represent a major challenge to SC survival in nerve injury. LRP1 functions as a potent activator of PI3K in SCs and, by this mechanism, limits SC apoptosis resulting from increased CHOP expression in nerve injury.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Peripheral Nerve Injuries  ISOHspa5 (Rattus norvegicus)5685664; 5685664mRNA:increased expressionRGD 
Peripheral Nerve Injuries  IEP 5685664mRNA:increased expressionRGD 

Objects Annotated

Genes (Rattus norvegicus)
Hspa5  (heat shock protein family A (Hsp70) member 5)

Genes (Mus musculus)
Hspa5  (heat shock protein 5)

Genes (Homo sapiens)
HSPA5  (heat shock protein family A (Hsp70) member 5)


Additional Information