RGD Reference Report - Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1. - 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

Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1.

Authors: Atkin, JD  Farg, MA  Turner, BJ  Tomas, D  Lysaght, JA  Nunan, J  Rembach, A  Nagley, P  Beart, PM  Cheema, SS  Horne, MK 
Citation: Atkin JD, etal., J Biol Chem. 2006 Oct 6;281(40):30152-65. Epub 2006 Jul 17.
RGD ID: 2311466
Pubmed: PMID:16847061   (View Abstract at PubMed)
DOI: DOI:10.1074/jbc.M603393200   (Journal Full-text)

Mutations in Cu/Zn superoxide dismutase (SOD1) are linked to motor neuron death in familial amyotrophic lateral sclerosis (ALS) by an unclear mechanism, although misfolded SOD1 aggregates are commonly associated with disease. Proteomic analysis of the transgenic SOD1(G93A) ALS rat model revealed significant up-regulation of endoplasmic reticulum (ER)-resident protein-disulfide isomerase (PDI) family members in lumbar spinal cords. Expression of SOD1 mutants (mSOD1) led to an up-regulation of PDI in motor neuron-like NSC-34 cells but not other cell lines. Inhibition of PDI using bacitracin increased aggregate production, even in wild type SOD1 transfectants that do not readily form inclusions, suggesting PDI may protect SOD1 from aggregation. Moreover, PDI co-localized with intracellular aggregates of mSOD1 and bound to both wild type and mSOD1. SOD1 was also found in the microsomal fraction of cells despite being a predominantly cytosolic enzyme, confirming ER-Golgi-dependent secretion. In SOD1(G93A) mice, a significant up-regulation of unfolded protein response entities was also observed during disease, including caspase-12, -9, and -3 cleavage. Our findings therefore implicate unfolded protein response and ER stress-induced apoptosis in the patho-physiology of familial ALS. The possibility that PDI may be a therapeutic target to prevent SOD1 aggregation is also raised by this study.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
amyotrophic lateral sclerosis  ISOCasp12 (Rattus norvegicus)2311466; 2311466protein:increased activity:spinal cordRGD 
amyotrophic lateral sclerosis  ISOCasp3 (Rattus norvegicus)2311466; 2311466protein:increased activity:spinal cordRGD 
amyotrophic lateral sclerosis  ISOCasp9 (Rattus norvegicus)2311466; 2311466protein:increased activity:spinal cordRGD 
amyotrophic lateral sclerosis  IEP 2311466; 2311466; 2311466protein:increased activity:spinal cordRGD 

Objects Annotated

Genes (Rattus norvegicus)
Casp12  (caspase 12)
Casp3  (caspase 3)
Casp9  (caspase 9)

Genes (Mus musculus)
Casp12  (caspase 12)
Casp3  (caspase 3)
Casp9  (caspase 9)

Genes (Homo sapiens)
CASP12  (caspase 12 (gene/pseudogene))
CASP3  (caspase 3)
CASP9  (caspase 9)


Additional Information