RGD Reference Report - Altered longevity-assurance activity of p53:p44 in the mouse causes memory loss, neurodegeneration and premature death. - Rat Genome Database

Send us a Message
Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   
Search RGD Grant Resources Citing RGD About Us Contact Us
Genes Variants Community Projects QTLs Strains Markers Genome Information Ontologies Cell Lines References Download Submit Data
OntoMate (Literature Search) JBrowse (Genome Browser) Synteny Browser (VCMap) Variant Visualizer Multi-Ontology Enrichment (MOET) Gene-Ortholog Location Finder (GOLF) InterViewer (Protein-Protein Interactions) PhenoMiner (Quatitative Phenotypes) Gene Annotator OLGA (Gene List Generator) AllianceMine GViewer (Genome Viewer)
Aging & Age-Related Disease Cancer & Neoplastic Disease Cardiovascular Disease Coronavirus Disease Developmental Disease Diabetes Hematologic Disease Immune & Inflammatory Disease Infectious Disease Liver Disease Neurological Disease Obesity & Metabolic Syndrome Renal Disease Respiratory Disease Sensory Organ Disease
Find Models   new Genetic Models Autism Models Rat PhenoMiner (Quantitative Phenotypes) Chinchilla PhenoMiner Expected Ranges (Quantitative Phenotype) PhenoMiner Term Comparison Hybrid Rat Diversity Panel Phenotypes Phenotypes in Other Animal Models Animal Husbandry Strain Medical Records Phylogenetics Strain Availability Calendar Rats 101 Submissions Photo Archive
Pathways
Rat Community Forum Directory of Rat Laboratories Video Tutorials News RGD Publications RGD Presentations Archive Nomenclature Guidelines Resource Links Laboratory Resources Employment Resources

Altered longevity-assurance activity of p53:p44 in the mouse causes memory loss, neurodegeneration and premature death.

Authors: Pehar, M  O'Riordan, KJ  Burns-Cusato, M  Andrzejewski, ME  Del Alcazar, CG  Burger, C  Scrable, H  Puglielli, L 
Citation: Pehar M, etal., Aging Cell. 2010 Apr;9(2):174-90.
RGD ID: 5686420
Pubmed: PMID:20409077   (View Abstract at PubMed)
PMCID: PMC2848983   (View Article at PubMed Central)
DOI: DOI:10.1111/j.1474-9726.2010.00547.x   (Journal Full-text)

The longevity-assurance activity of the tumor suppressor p53 depends on the levels of Delta40p53 (p44), a short and naturally occurring isoform of the p53 gene. As such, increased dosage of p44 in the mouse leads to accelerated aging and short lifespan. Here we show that mice homozygous for a transgene encoding p44 (p44(+/+)) display cognitive decline and synaptic impairment early in life. The synaptic deficits are attributed to hyperactivation of insulin-like growth factor 1 receptor (IGF-1R) signaling and altered metabolism of the microtubule-binding protein tau. In fact, they were rescued by either Igf1r or Mapt haploinsufficiency. When expressing a human or a 'humanized' form of the amyloid precursor protein (APP), p44(+/+) animals developed a selective degeneration of memory-forming and -retrieving areas of the brain, and died prematurely. Mechanistically, the neurodegeneration was caused by both paraptosis- and autophagy-like cell deaths. These results indicate that altered longevity-assurance activity of p53:p44 causes memory loss and neurodegeneration by affecting IGF-1R signaling. Importantly, Igf1r haploinsufficiency was also able to correct the synaptic deficits of APP(695/swe) mice, a model of Alzheimer's disease.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Alzheimer's disease  ISOIgf1r (Mus musculus)5686420; 5686420DNA: haploinsufficiency:: full knockout dies at birthRGD 
Alzheimer's disease  IAGP 5686420DNA: haploinsufficiency:: full knockout dies at birthRGD 

Objects Annotated

Genes (Rattus norvegicus)
Igf1r  (insulin-like growth factor 1 receptor)

Genes (Mus musculus)
Igf1r  (insulin-like growth factor I receptor)

Genes (Homo sapiens)
IGF1R  (insulin like growth factor 1 receptor)


Additional Information