Neuronal co-expression of EGFP and β-galactosidase in mice causes neuropathology and premature death

Abstract

Dose-dependent co-expression of enhanced green fluorescent protein (EGFP) and β-galactosidase (β-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 β-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 β-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 β-gal-induced dysfunction, as demise of mice started after treatment was discontinued.

Keywords

• Cytoplasmic GFP and β-gal
• GCSF and minocycline
• Neurogenic paresis
• Protein aggregates
• Ubiquitin