Autophagy is a prosurvival mechanism in cells expressing an autosomal dominant familial neurohypophyseal diabetes insipidus mutant vasopressin transgene

被引:37
作者
Castino, R
Davies, J
Beaucourt, S
Isidoro, C
Murphy, D
机构
[1] Univ Bristol, Mol Neuroendocrinol Res GRp, Henry Wellcome Labs Integrat Neurosci & Endocrino, Bristol BS1 3NY, Avon, England
[2] Amedeo Avogadro Univ, Dept Med Sci, Lab Mol Pathol, I-28100 Novara, Italy
关键词
apoptosis; transgenic; adFNDI; antidiuretic hormone; VP;
D O I
10.1096/fj.04-3162fje
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-Cys67 stop) 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-Cys67 stop 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-Cys67 stop expression. These data suggest that activation of autophagy by the stress of the expression of an adFNDI mutant protein is a prosurvival mechanism.
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页码:1021 / +
页数:21
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