RGD Reference Report - The Fas/Fas ligand death receptor pathway contributes to phenylalanine-induced apoptosis in cortical neurons. - Rat Genome Database

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The Fas/Fas ligand death receptor pathway contributes to phenylalanine-induced apoptosis in cortical neurons.

Authors: Huang, X  Lu, Z  Lv, Z  Yu, T  Yang, P  Shen, Y  Ding, Y  Fu, D  Zhang, X  Fu, Q  Yu, Y 
Citation: Huang X, etal., PLoS One. 2013 Aug 7;8(8):e71553. doi: 10.1371/journal.pone.0071553. Print 2013.
RGD ID: 8663468
Pubmed: PMID:23940767   (View Abstract at PubMed)
PMCID: PMC3737091   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0071553   (Journal Full-text)

Phenylketonuria (PKU), an autosomal recessive disorder of amino acid metabolism caused by mutations in the phenylalanine hydroxylase (PAH) gene, leads to childhood mental retardation by exposing neurons to cytotoxic levels of phenylalanine (Phe). A recent study showed that the mitochondria-mediated (intrinsic) apoptotic pathway is involved in Phe-induced apoptosis in cultured cortical neurons, but it is not known if the death receptor (extrinsic) apoptotic pathway and endoplasmic reticulum (ER) stress-associated apoptosis also contribute to neurodegeneration in PKU. To answer this question, we used specific inhibitors to block each apoptotic pathway in cortical neurons under neurotoxic levels of Phe. The caspase-8 inhibitor Z-IETD-FMK strongly attenuated apoptosis in Phe-treated neurons (0.9 mM, 18 h), suggesting involvement of the Fas receptor (FasR)-mediated cell death receptor pathway in Phe toxicity. In addition, Phe significantly increased cell surface Fas expression and formation of the Fas/FasL complex. Blocking Fas/FasL signaling using an anti-Fas antibody markedly inhibited apoptosis caused by Phe. In contrast, blocking the ER stress-induced cell death pathway with salubrinal had no effect on apoptosis in Phe-treated cortical neurons. These experiments demonstrate that the Fas death receptor pathway contributes to Phe-induced apoptosis and suggest that inhibition of the death receptor pathway may be a novel target for neuroprotection in PKU patients.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
FasRatcellular response to phenylalanine  IEP  RGD 
FasRatpositive regulation of neuron apoptotic process  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Fas  (Fas cell surface death receptor)


Additional Information