RGD Reference Report - Chronic and acute models of retinal neurodegeneration TrkA activity are neuroprotective whereas p75NTR activity is neurotoxic through a paracrine mechanism. - Rat Genome Database

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Chronic and acute models of retinal neurodegeneration TrkA activity are neuroprotective whereas p75NTR activity is neurotoxic through a paracrine mechanism.

Authors: Bai, Y  Dergham, P  Nedev, H  Xu, J  Galan, A  Rivera, JC  ZhiHua, S  Mehta, HM  Woo, SB  Sarunic, MV  Neet, KE  Saragovi, HU 
Citation: Bai Y, etal., J Biol Chem. 2010 Dec 10;285(50):39392-400. Epub 2010 Oct 13.
RGD ID: 5508695
Pubmed: PMID:20943663   (View Abstract at PubMed)
PMCID: PMC2998128   (View Article at PubMed Central)
DOI: DOI:10.1074/jbc.M110.147801   (Journal Full-text)

In normal adult retinas, NGF receptor TrkA is expressed in retinal ganglion cells (RGC), whereas glia express p75(NTR). During retinal injury, endogenous NGF, TrkA, and p75(NTR) are up-regulated. Paradoxically, neither endogenous NGF nor exogenous administration of wild type NGF can protect degenerating RGCs, even when administered at high frequency. Here we elucidate the relative contribution of NGF and each of its receptors to RGC degeneration in vivo. During retinal degeneration due to glaucoma or optic nerve transection, treatment with a mutant NGF that only activates TrkA, or with a biological response modifier that prevents endogenous NGF and pro-NGF from binding to p75(NTR) affords significant neuroprotection. Treatment of normal eyes with an NGF mutant-selective p75(NTR) agonist causes progressive RGC death, and in injured eyes it accelerates RGC death. The mechanism of p75(NTR) action during retinal degeneration due to glaucoma is paracrine, by increasing production of neurotoxic proteins TNF-alpha and alpha(2)-macroglobulin. Antagonists of p75(NTR) inhibit TNF-alpha and alpha(2)-macroglobulin up-regulation during disease, and afford neuroprotection. These data reveal a balance of neuroprotective and neurotoxic mechanisms in normal and diseased retinas, and validate each neurotrophin receptor as a pharmacological target for neuroprotection.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
negative regulation of cellular process  IDA 5508695retinal ganglion cellsRGD 
positive regulation of cellular process  IDA 5508695retinal ganglion cellsRGD 

Objects Annotated

Genes (Rattus norvegicus)
Ngfr  (nerve growth factor receptor)
Ntrk1  (neurotrophic receptor tyrosine kinase 1)

Genes (Mus musculus)
Ngfr  (nerve growth factor receptor (TNFR superfamily, member 16))
Ntrk1  (neurotrophic tyrosine kinase, receptor, type 1)

Genes (Homo sapiens)
NGFR  (nerve growth factor receptor)
NTRK1  (neurotrophic receptor tyrosine kinase 1)


Additional Information