Autophagy-dependent cell survival and cell death in an autosomal dominant familial neurohypophyseal diabetes insipidus in vitro model

FASEB J. 2005 Jun;19(8):1024-6. doi: 10.1096/fj.04-3163fje. Epub 2005 Mar 21.


Mutations in the human gene encoding the antidiuretic hormone vasopressin (VP) cause autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI), a rare inherited disorder that presents as polydipsia and polyuria as a consequence of a loss of secretion of VP from posterior pituitary nerve terminals. Work from our laboratories has shown that adFNDI, like other neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's, is associated with autophagy. We have recently shown that the activation of autophagy in mouse neuroblastoma Neuro2a cells after adenoviral vector-mediated delivery of an adFNDI mutant VP transgene (Cys67stop) is a cell survival mechanism; its inhibition induces apoptosis. We now show that expression of Cys67stop sensitizes Neuro2a cells to the lethal effects of dopamine. This mode of cell death exhibits features typically associated with classical apoptosis. Yet inhibition of autophagy reversed these effects and rescued cell viability. We propose that autophagy-mediated cell death is a "two-hit" process: Following the cellular stress of the accumulation of a misfolded mutant protein, autophagy is prosurvival. However, a second insult triggers an autophagy-dependent apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Autophagy / physiology*
  • Cadaverine / analogs & derivatives
  • Caspases / metabolism
  • Cell Death / drug effects
  • Cell Death / physiology*
  • Cell Line, Tumor
  • Cell Survival / physiology*
  • Codon, Terminator / genetics
  • Cysteine / genetics
  • Diabetes Insipidus, Neurogenic / genetics*
  • Diabetes Insipidus, Neurogenic / pathology*
  • Disease Models, Animal
  • Dopamine / pharmacology
  • Fluorescent Dyes
  • Gene Expression
  • Genetic Vectors
  • Mice
  • Mutation
  • Neuroblastoma
  • Phagosomes / ultrastructure
  • Transfection
  • Transgenes / genetics
  • Vacuoles
  • Vasopressins / genetics


  • Codon, Terminator
  • Fluorescent Dyes
  • Vasopressins
  • Caspases
  • monodansylcadaverine
  • Cysteine
  • Cadaverine
  • Dopamine