A novel mechanism of autophagy-associated cell death of vasopressin neurons in familial neurohypophysial diabetes insipidus

Abstract

Familial neurohypophysial diabetes insipidus (FNDI), characterized by delayed-onset progressive polyuria and loss of arginine vasopressin (AVP) neuron, is an autosomal dominant disorder caused by AVP gene mutations. We previously generated a knock-in mouse model for FNDI, which recapitulated the phenotype of human FNDI. To address the mechanisms underlying AVP neuron loss, we subjected FNDI mice to intermittent water deprivation, which accelerated the phenotype and induced AVP neuron loss within a relative short period. Electron microscopic analyses revealed that aggregates were confined to a sub-compartment of the endoplasmic reticulum (ER), ER-associated compartment (ERAC), in AVP neurons of FNDI mice under normal conditions. In contrast, aggregates scattered throughout the dilated ER lumen, and phagophores, autophagosome precursors, emerged and surrounded the ER containing scattered aggregates in FNDI mice subjected to water deprivation for 4 weeks, suggesting that failure of ERAC formation leads to autophagy induction for degradation of aggregates. Furthermore, the cytoplasm was entirely occupied with large vacuoles in AVP neurons of FNDI mice subjected to water deprivation for 12 weeks, at which stage 30-40% of AVP neurons were lost. Our data demonstrated that although autophagy should primarily be a protective mechanism, continuous autophagy leads to gradual loss of organelles including ER, resulting in autophagy-associated cell death of AVP neurons in FNDI mice.

Familial neurohypophyseal diabetes insipidus in 13 kindreds and 2 novel mutations in the vasopressin gene

“…The late onset of the disease in family 12 may be explained by the fact that this new mutation causes a switch among neutral amino acids, which potentially does not severely affect the biochemical features of the mature protein. The hypothesized mechanisms underlying the phenotype of the two novel mutations could be explained by one of those extensively investigated in the cell lines of patients with adNDI (8,16,17,33). Mutant AVP precursors reportedly accumulate and aggregate in the ER, which leads to defective intracellular trafficking of wild-type AVP protein and a decrease in cell viability.…”

“…Mutant AVP precursors reportedly accumulate and aggregate in the ER, which leads to defective intracellular trafficking of wild-type AVP protein and a decrease in cell viability. Furthermore, autophagy has been suggested to have a bifunctional role in cell survival and death in a transfected cell lineexpressing mutant NPII (40,41) resulting in autophagy-associated cell death of AVP neurons in mice with familial NDI mice (33). In autosomal dominant CDI, clinical disease onset can be expressed during the neonatal period (8,10), but typically polyuria and polydipsia in adNDI occur during the first months to years of life and progress as AVP deficiency becomes increasingly severe (8).…”

“…The wide variability in the age of onset and the severity of the AVP deficiency among patients with the same mutation may be ascribed to individual differences among such patients, like the rate of production of the mutant precursor, the intensity of neurohypophyseal stimulation, individual susceptibility to the toxic effect of the mutant precursor, the ability to degrade mutant precursors and variations in secretory reserve capacity or in the development of the gland itself (8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30). Recent data demonstrated that although autophagy should primarily be a protective mechanism, continuous autophagy leads to gradual loss of organelles including endoplasmic reticulum (ER), resulting in autophagyassociated cell death of AVP neurons in mice with familial NDI (33).…”

Central Diabetes Insipidus Caused by Arginine Vasopressin Gene Mutation: Report of a Novel Mutation and Review of Literature

“…The other part of the mutants is eliminated via ER-associated degradation (ERAD) by proteasomes after retro-translocation to the cytosol [59]. Hagiwara et al recently showed that autophagy should be primarily a protective mechanism, but continuous autophagy leads to a gradual loss of organelles, including the ER, resulting in autophagy-associated cell death of AVP neurons in mice with FNDI [60]. Although the possible loss of vasopressinergic neurons is associated with autophagy, the mechanism leading to cell degeneration in autosomal dominant FNDI is still unknown.…”

Degradation of Mutant Protein Aggregates within the Endoplasmic Reticulum of Vasopressin Neurons

“…We previously reported that macroautophagy or cell death was not observed as long as mutant NPII was confined to the ERACs in FNDI mice with free access to water (Hagiwara et al, 2014). Conversely, ERAC ll OPEN ACCESS iScience Article formation was disrupted and mutant NPII aggregates were spread throughout the ER lumen after intermittent water deprivation, leading to autophagy-associated cell death of AVP neurons in FNDI mice (Hagiwara et al, 2014(Hagiwara et al, , 2019. Taken together, it seems that ERAC formation as well as degradation of mutant proteins within ERACs is essential for protecting AVP neurons from cell death in FNDI.…”