RGD Reference Report - alpha-Synuclein is involved in manganese-induced ER stress via PERK signal pathway in organotypic brain slice cultures. - Rat Genome Database

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alpha-Synuclein is involved in manganese-induced ER stress via PERK signal pathway in organotypic brain slice cultures.

Authors: Xu, B  Wang, F  Wu, SW  Deng, Y  Liu, W  Feng, S  Yang, TY  Xu, ZF 
Citation: Xu B, etal., Mol Neurobiol. 2014 Feb;49(1):399-412. doi: 10.1007/s12035-013-8527-2. Epub 2013 Aug 10.
RGD ID: 10047151
Pubmed: PMID:23934647   (View Abstract at PubMed)
DOI: DOI:10.1007/s12035-013-8527-2   (Journal Full-text)

Overexposure to manganese (Mn) has been known to induce neuronal damage involving endoplasmic reticulum (ER) stress. However, the exact mechanism of Mn-induced ER stress is unclear. Increasing evidence suggested that the overexpression of alpha-synuclein played a critical role in Mn-induced neurotoxicity. To explore whether the occurrence of ER stress was associated with alpha-synuclein overexpression, we made the rat brain slices model of silencing alpha-synuclein using short-interference RNA. After non-silencing alpha-synuclein slices were treated with Mn (0-400 muM) for 24 h, there was a dose-dependent increase in apoptotic rates of cells and levels of lactate dehydrogenase in the culture medium. Moreover, there was a dose-dependent increase in the protein expression of 78, 94-kDa glucose-regulated protein (GRP78/94), C/EBP homologous protein (CHOP), and caspase-12. Moreover, PKR-like ER kinase (PERK) phosphorylation, PERK-mediated phosphorylation of eIF2a, and ATF4 expression also increased. Inositol-requiring enzyme 1 (IRE1) activation and X-box-binding protein-1 (Xbp1) mRNA splicing increased. Activating transcription factor 6 p90 levels did not change. However, after silencing alpha-synuclein slices were treated with 400 muM Mn for 24 h, there was a significant decrease in the expression of GRP78/94, CHOP, and caspase-12 compared with 400 muM Mn-treated non-silencing alpha-synuclein slices. Furthermore, PERK phosphorylation, PERK-mediated phosphorylation of eIF2a, and ATF4 mRNA expression also decreased. However, IRE1 phosphorylation and Xbp1 mRNA splicing did not change. The findings revealed that Mn induced ER stress via activation of PERK and IRE1 signaling pathways and subsequent apoptosis in cultured slices. Moreover, alpha-synuclein protein was associated with Mn-induced activation of PERK signaling pathway.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Casp12Ratcellular response to manganese ion involved_inIEP PMID:23934647ParkinsonsUK-UCL 
Ddit3Ratcellular response to manganese ion involved_inIEP PMID:23934647ParkinsonsUK-UCL 
Ern1Ratcellular response to manganese ion involved_inIEP PMID:23934647ParkinsonsUK-UCL 
Hsp90b1Ratcellular response to manganese ion involved_inIEP PMID:23934647ParkinsonsUK-UCL 
Hspa5Ratcellular response to manganese ion involved_inIEP PMID:23934647ParkinsonsUK-UCL 
Atf4Ratresponse to manganese-induced endoplasmic reticulum stress involved_inIEP PMID:23934647ParkinsonsUK-UCL 
Eif2ak3Ratresponse to manganese-induced endoplasmic reticulum stress involved_inIEP PMID:23934647ParkinsonsUK-UCL 
Eif2s1Ratresponse to manganese-induced endoplasmic reticulum stress involved_inIEP PMID:23934647ParkinsonsUK-UCL 

Objects Annotated

Genes (Rattus norvegicus)
Atf4  (activating transcription factor 4)
Casp12  (caspase 12)
Ddit3  (DNA-damage inducible transcript 3)
Eif2ak3  (eukaryotic translation initiation factor 2 alpha kinase 3)
Eif2s1  (eukaryotic translation initiation factor 2 subunit alpha)
Ern1  (endoplasmic reticulum to nucleus signaling 1)
Hsp90b1  (heat shock protein 90 beta family member 1)
Hspa5  (heat shock protein family A (Hsp70) member 5)


Additional Information