title: Arginine vasopressin neuronal loss results from autophagy-associated cell death in a mouse model for familial neurohypophysial diabetes insipidus.
abstract: Familial neurohypophysial diabetes insipidus (FNDI) characterized by progressive polyuria is mostly caused by mutations in the gene encoding neurophysin II (NPII), which is the carrier protein of the antidiuretic hormone, arginine vasopressin (AVP). Although accumulation of mutant NPII in the endoplasmic reticulum (ER) could be toxic for AVP neurons, the precise mechanisms of cell death of AVP neurons, reported in autopsy studies, remain unclear. Here, we subjected FNDI model mice to intermittent water deprivation (WD) in order to promote the phenotypes. Electron microscopic analyses demonstrated that, while aggregates are confined to a certain compartment of the ER in the AVP neurons of FNDI mice with water access ad libitum, they were scattered throughout the dilated ER lumen in the FNDI mice subjected to WD for 4 weeks. It is also demonstrated that phagophores, the autophagosome precursors, emerged in the vicinity of aggregates and engulfed the ER containing scattered aggregates. Immunohistochemical analyses revealed that expression of p62, an adapter protein between ubiquitin and autophagosome, was elicited on autophagosomal membranes in the AVP neurons, suggesting selective autophagy induction at this time point. Treatment of hypothalamic explants of green fluorescent protein (GFP)-microtubule-associated protein 1 light chain 3 (LC3) transgenic mice with an ER stressor thapsigargin increased the number of GFP-LC3 puncta, suggesting that ER stress could induce autophagosome formation in the hypothalamus of wild-type mice as well. The cytoplasm of AVP neurons in FNDI mice was occupied with vacuoles in the mice subjected to WD for 12 weeks, when 30-40% of AVP neurons are lost. Our data thus demonstrated that autophagy was induced in the AVP neurons subjected to ER stress in FNDI mice. Although autophagy should primarily be protective for neurons, it is suggested that the organelles including ER were lost over time through autophagy, leading to autophagy-associated cell death of AVP neurons.
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: D
authors.initials: D
authors.lastname: Hagiwara
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Arima
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Morishita
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: L
authors.initials: L
authors.lastname: Wenjun
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Azuma
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Suga
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Goto
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Banno
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Sugimura
authors.affiliation: PhoenixBio Co. Ltd, Utsunomiya, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Shiota
authors.affiliation: Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Asai
authors.affiliation: Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Oiso
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001127:Arginine Vasopressin / Q000378:metabolism*; D001343:Autophagy; D020790:Diabetes Insipidus, Neurogenic / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D059865:Endoplasmic Reticulum Stress; D006360:Heat-Shock Proteins / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism / Q000473:pathology; D002479:Inclusion Bodies / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D010588:Phagosomes / Q000378:metabolism / Q000648:ultrastructure; D010641:Phenotype; D066329:Protein Aggregates; D000071456:Sequestosome-1 Protein; D057149:Ubiquitinated Proteins / Q000378:metabolism; D014868:Water Deprivation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D066329:Protein Aggregates; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D057149:Ubiquitinated Proteins; D001127:Arginine Vasopressin