Autophagy is a prosurvival mechanism in cells expressing an autosomal dominant familial neurohypophyseal diabetes insipidus mutant vasopressin transgene
| Autor: | Stephanie Beaucourt, Roberta Castino, David Murphy, Ciro Isidoro, Janet E. Davies |
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| Rok vydání: | 2005 |
| Předmět: |
Programmed cell death
medicine.medical_specialty Vasopressins Transgene Blotting Western Genetic Vectors Fluorescent Antibody Technique Gene Expression Vacuole Gene mutation Biology Transfection Cathepsin D Biochemistry Adenoviridae Animals Genetically Modified Neuroblastoma Mutant protein Cadaverine Cell Line Tumor Internal medicine Autophagy Neurites Genetics medicine Animals Secretion Cysteine Transgenes Molecular Biology Fluorescent Dyes Neurons Organelles Hydrogen-Ion Concentration Acridine Orange Recombinant Proteins Rats Cell biology Diabetes Insipidus Neurogenic Endocrinology Mutation Vacuoles Codon Terminator Lysosomes Intracellular Biotechnology |
| Zdroj: | The FASEB Journal. 19:1021-1023 |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.04-3162fje |
| Popis: | Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is a progressive, inherited neurodegenerative disorder that presents as polydipsia and polyuria as a consequence of a loss of secretion of the antidiuretic hormone vasopressin (VP) from posterior pituitary nerve terminals. VP gene mutations cause adFNDI. Rats expressing an adFNDI VP transgene (Cys67stop) show a neuronal pathology characterized by autophagic structures in the cell body. adFNDI has thus been added to the list of protein aggregation diseases, along with Alzheimer's, Parkinson's and Huntington's, which are associated with autophagy, a bulk process that delivers regions of cytosol to lysosomes for degradation. However, the role of autophagy in these diseases is unclear. To address the relationships between mutant protein accumulation, autophagy, cell survival, and cell death, we have developed a novel and tractable in vitro system. We have constructed adenoviral vectors (Ads) that express structural genes encoding either the Cys67stop mutant protein (Ad-VCAT-Cys67stop) or an epitope-tagged wild-type VP precursor (Ad-VCAT). After infection of mouse neuroblastoma Neuro2a cells, Ad-VCAT encoded material enters neurite processes and accumulates in terminals, while the Cys67stop protein is confined to enlarged vesicles in the cell body. Similar to the intracellular derangements seen in the Cys67stop rats, these structures are of ER origin, and colocalize with markers of autophagy. Neither Ad-VCAT-Cys67stop nor Ad-VCAT expression affected cell viability. However, inhibition of autophagy or lysosomal protein degradation, while having no effect on Ad-VCAT-expressing cells, significantly increased apoptotic cell death following Ad-VCAT-Cys67stop expression. These data suggest that activation of autophagy by the stress of the expression of an adFNDI mutant protein is a prosurvival mechanism. |
| Databáze: | OpenAIRE |
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