Neuronal over-expression of chromogranin A accelerates disease onset in a mouse model of ALS.
Recent studies provided evidence that chromogranins can interact with mutant superoxide dismutase 1 (SOD1) and that chromogranin B (CgB) may act as a susceptibility gene and modifier of onset in amyotrophic lateral sclerosis (ALS). To further investigate the role of chromogranins in ALS pathogenesis, we generated SOD1(G37R) mice that over-express CgA under the control of Thy1 promoter. Here, we report that neuronal over-expression of CgA in SOD1(G37R) mice caused acceleration of onset of motor impairment and exacerbation of motor neuron degeneration. The use of monoclonal antibody specific to misfolded mutant SOD1 demonstrated a higher level of misfolded SOD1 species in double transgenic mice compared to SOD1(G37R) mice, suggesting a stabilization of pathogenic SOD1 species by excess CgA. These results suggest a role of chromogranins as modulators of disease onset in ALS pathogenesis.
Ezzi
Samer Abou
SA
Centre de Recherche du Centre Hospitalier Universitaire de Québec, Laval University, Quebec, Quebec, Canada.
Larivière
Roxanne
R
Urushitani
Makoto
M
Julien
Jean-Pierre
JP
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D002470:Cell Survival; D053379:Chromogranin A / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D009469:Neuromuscular Junction / Q000473:pathology; D017510:Protein Folding; D013116:Spinal Cord / Q000473:pathology*; D013482:Superoxide Dismutase / Q000235:genetics; D018800:Thy-1 Antigens / Q000235:genetics
D053379:Chromogranin A; D005904:Glial Fibrillary Acidic Protein; D018800:Thy-1 Antigens; C470429:SOD1 G37R protein, mouse; D013482:Superoxide Dismutase