RGD Reference Report - Notch pathway is activated in cell culture and mouse models of mutant SOD1-related familial amyotrophic lateral sclerosis, with suppression of its activation as an additional mechanism of neuroprotection for lithium and valproate. - Rat Genome Database

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Notch pathway is activated in cell culture and mouse models of mutant SOD1-related familial amyotrophic lateral sclerosis, with suppression of its activation as an additional mechanism of neuroprotection for lithium and valproate.

Authors: Wang, S-Y  Ren, M  Jiang, H-Z  Wang, J  Jiang, H-Q  Yin, X  Qi, Y  Wang, X-D  Dong, G-T  Wang, T-H  Yang, Y-Q  Feng, H-L 
Citation: Wang SY, etal., Neuroscience. 2015 Aug 20;301:276-88. doi: 10.1016/j.neuroscience.2015.06.002. Epub 2015 Jun 8.
RGD ID: 13524575
Pubmed: PMID:26067594   (View Abstract at PubMed)
DOI: DOI:10.1016/j.neuroscience.2015.06.002   (Journal Full-text)

Amyotrophic lateral sclerosis (ALS) is an idiopathic and lethal neurodegenerative disease that currently has no effective treatment. A recent study found that the Notch signaling pathway was up-regulated in a TAR DNA-binding protein-43 (TDP-43) Drosophila model of ALS. Notch signaling acts as a master regulator in the central nervous system. However, the mechanisms by which Notch participates in the pathogenesis of ALS have not been completely elucidated. Recent studies have shown that the mood stabilizers lithium and valproic acid (VPA) are able to regulate Notch signaling. Our study sought to confirm the relationship between the Notch pathway and ALS and whether the Notch pathway contributes to the neuroprotective effects of lithium and VPA in ALS. We found that the Notch pathway was activated in in vitro and in vivo models of ALS, and suppression of Notch activation with a Notch signaling inhibitor, N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT) and Notch1 siRNA significantly reduced neuronal apoptotic signaling, as evidenced by the up-regulation of Bcl-2 as well as the down-regulation of Bax and cytochrome c. We also found that lithium and VPA suppressed the Notch activation associated with the superoxide dismutase-1 (SOD1) mutation, and the combination of lithium and VPA produced a more robust effect than either agent alone. Our findings indicate that the Notch pathway plays a critical role in ALS, and the neuroprotective effects of lithium and VPA against mutant SOD1-mediated neuronal damage are at least partially dependent on their suppression of Notch activation.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
HES1Humanamyotrophic lateral sclerosis  ISOHes1 (Mus musculus)protein:increased expression:spinal chordRGD 
HEY1Humanamyotrophic lateral sclerosis  ISOHey1 (Mus musculus)protein:increased expression:spinal chordRGD 
Hes1Ratamyotrophic lateral sclerosis  ISOHes1 (Mus musculus)protein:increased expression:spinal chordRGD 
Hes1Mouseamyotrophic lateral sclerosis  IEP protein:increased expression:spinal chordRGD 
Hey1Ratamyotrophic lateral sclerosis  ISOHey1 (Mus musculus)protein:increased expression:spinal chordRGD 
Hey1Mouseamyotrophic lateral sclerosis  IEP protein:increased expression:spinal chordRGD 
JAG1Humanamyotrophic lateral sclerosis  ISOJag1 (Mus musculus)protein:increased expression:spinal chordRGD 
Jag1Ratamyotrophic lateral sclerosis  ISOJag1 (Mus musculus)protein:increased expression:spinal chordRGD 
Jag1Mouseamyotrophic lateral sclerosis  IEP protein:increased expression:spinal chordRGD 
MAML1Humanamyotrophic lateral sclerosis  ISOMaml1 (Mus musculus)protein:increased expression:spinal chordRGD 
Maml1Ratamyotrophic lateral sclerosis  ISOMaml1 (Mus musculus)protein:increased expression:spinal chordRGD 
Maml1Mouseamyotrophic lateral sclerosis  IEP protein:increased expression:spinal chordRGD 
NOTCH1Humanamyotrophic lateral sclerosis  ISONotch1 (Mus musculus)protein:increased expression:spinal chordRGD 
Notch1Ratamyotrophic lateral sclerosis  ISONotch1 (Mus musculus)protein:increased expression:spinal chordRGD 
Notch1Mouseamyotrophic lateral sclerosis  IEP protein:increased expression:spinal chordRGD 

Objects Annotated

Genes (Rattus norvegicus)
Hes1  (hes family bHLH transcription factor 1)
Hey1  (hes-related family bHLH transcription factor with YRPW motif 1)
Jag1  (jagged canonical Notch ligand 1)
Maml1  (mastermind-like transcriptional coactivator 1)
Notch1  (notch receptor 1)

Genes (Mus musculus)
Hes1  (hes family bHLH transcription factor 1)
Hey1  (hairy/enhancer-of-split related with YRPW motif 1)
Jag1  (jagged 1)
Maml1  (mastermind like transcriptional coactivator 1)
Notch1  (notch 1)

Genes (Homo sapiens)
HES1  (hes family bHLH transcription factor 1)
HEY1  (hes related family bHLH transcription factor with YRPW motif 1)
JAG1  (jagged canonical Notch ligand 1)
MAML1  (mastermind like transcriptional coactivator 1)
NOTCH1  (notch receptor 1)


Additional Information