Neuronal co-expression of EGFP and beta-galactosidase in mice causes neuropathology and premature death.
Dose-dependent co-expression of enhanced green fluorescent protein (EGFP) and beta-galactosidase (beta-gal) in the cytoplasm of forebrain neurons of two independent mouse lines resulted in growth retardation, weakness, and premature lethality. In primary motor cortex and striatum, apoptosis, glial fibrillary acidic protein proliferation, and cell loss were found. In addition, we observed aggregations of EGFP and beta-gal that colocalized with ubiquitin. GFP is unlikely to be toxic per se, as a third mouse line that expressed twice as much GFP in the cytoplasm of forebrain neurons as the two affected lines was normal. Cytoplasmic aggregations of EGFP and beta-gal occurred in affected and phenotypically normal mice suggesting a storage function rather than being detrimental. We successfully prolonged survival of affected mice with granulocyte colony-stimulating factor (GCSF) and the antibiotic minocycline. These compounds could protect neurons from EGFP and beta-gal-induced dysfunction, as demise of mice started after treatment was discontinued.
Krestel
Heinz E
HE
Department of Molecular Neurobiology, Max-Planck-Institute for Medical Research, 69120 Heidelberg, Germany. Heinz.Krestel@pharma.unizh.ch
Mihaljevic
André L A
AL
Hoffman
Dax A
DA
Schneider
Armin
A
D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000473:pathology; D002455:Cell Division; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008911:Minocycline / Q000494:pharmacology; D009044:Motor Cortex / Q000473:pathology; D018908:Muscle Weakness / Q000209:etiology; D009422:Nervous System Diseases / Q000150:complications / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D009457:Neuroglia / Q000473:pathology; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010291:Paresis / Q000209:etiology; D013116:Spinal Cord / Q000473:pathology; D016019:Survival Analysis; D025801:Ubiquitin / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism*
D018696:Neuroprotective Agents; D025801:Ubiquitin; C485184:enhanced green fluorescent protein; D016179:Granulocyte Colony-Stimulating Factor; D049452:Green Fluorescent Proteins; D001616:beta-Galactosidase; D008911:Minocycline