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.

ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis

“…The majority of congenital neurogenic (central) diabetes insipidus cases occur as an autosomal-dominant disease, whereby any one of dozens of mutations in the AVP gene (e.g., G57S or ΔE47) cause ER retention of proAVP and the formation of fibrillar aggregates (2,(5)(6)(7)(8). Recent studies have shown that activation of autophagy and autophagy-associated neuronal death occur in response to proAVP aggregation at later stages of diabetes insipidus in mouse models subjected to intermittent water deprivation (9); however, the molecular mechanisms underlying physiological and pathophysiological proAVP folding and degradation remain to be explored. While both WT and mutant proAVP are subjected to proteasomal degradation (10), the nature and mechanisms of the degradative machinery (and, more importantly, the significance of this process in normal physiology and disease initiation) are totally unknown.…”

Central Diabetes Insipidus

“…31) The analyses of animal models for FNDI have demonstrated that accumulation of mutant AVP precursors in the endoplasmic reticulum (ER) causes ER stress and dysfunction of the neurons, which finally lead to loss of AVP neurons. [31][32][33] This is consistent with autopsy studies which showed that magnocellular neurons were lost in patients with FNDI. 34) TREATMENT Desmopressin, an analogue of AVP, is used for the treatment of CDI.…”

Central Diabetes Insipidus

“…[31][32][33] This is consistent with autopsy studies which showed that magnocellular neurons were lost in patients with FNDI. 34) TREATMENT Desmopressin, an analogue of AVP, is used for the treatment of CDI.…”