Endoplasmic reticulum derangement in hypothalamic neurons of rats expressing a familial neurohypophyseal diabetes insipidus mutant vasopressin transgene

Abstract

Human familial neurohypophyseal diabetes insipidus (FNDI) is an autosomal dominant endocrine disorder that presents in early childhood as excessive drinking and urination as a consequence of a progressive loss of secretion of vasopressin (VP) from posterior pituitary nerve terminals. Mutations in the VP gene have been implicated as the cause of FNDI, but the mechanisms by which these mutants manifest their pathology, and prevent the secretion of the co‐expressed wild‐type protein, are unknown. One hypothesis suggests that mutant precursors are toxic, and stop the synthesis of wild‐type VP by killing expressing cells. Another hypothesis suggests that aberrant interactions between mutant and wild‐type precursors might directly inhibit the elaboration or secretion of the products of the normal allele. We have tested these hypotheses using new animal models‐‐transgenic rats that express an FNDI mutant VP gene that encodes a truncated precursor (Cys67stop). Cell‐specific and inducible expression of the Cys67stop mutation in rat VP hypothalamic neurons does not result in cell death or atrophy. Rather, expression of the FNDI mutant causes a neuronal pathology characterized by distorted structures in the cell body that are labeled by antisera that recognize endoplasmic reticulum (ER) markers, and that accumulate both mutant and wild‐type VP gene products. This is accompanied by an increase in the abundance of the mannose‐6‐phosphate receptor (MPR), a marker of endosome‐lysosome activity. We suggest that FNDI in humans may be initiated, as in our transgenic rat model, by the trapping of wild‐type VP gene products within an ER, which is targeted for lysosomal degradation by autophagy.

Diabetes Insipidus: A Review

“…Rather, in some cases, due to the buildup and entrapment of the misfolded proteins, normal selective degradation of proteins can be overwhelmed. In its place, a non-selective degradation takes place, destroying both ADH proper and misfolded protein alike [48,49]. Autosomal recessive (AR) CDI is caused by a missense mutation, changing the position-7 proline to leucine.…”

Dominant pro-vasopressin mutants that cause diabetes insipidus form disulfide-linked fibrillar aggregates in the endoplasmic reticulum

“…However, aggregateproducing cells might have been rapidly eliminated. By contrast, vasopressinergic neurons expressing the same C67X mutant in transgenic rats were resistant to a cytotoxic effect, but produced distended ER structures containing the mutant protein and markers of autophagy (Davies and Murphy, 2002;Si-Hoe et al, 2000). This lysosomal degradation mechanism is thought to protect against the toxic effects of altered or aggregated intracellular proteins (Martinez-Vicente and Cuervo, 2007).…”

Identification of a novel mutation in the arginine vasopressin-neurophysin II gene affecting the sixth intrachain disulfide bridge of the neurophysin II moiety

“…The C98stop mutation determined an early onset of diabetes insipidus and a markedly worse phenotype in mice than the [A(-1)T] mutation (20), similarly to that which occurs in humans. The mutated protein accumulated in the endoplasmic reticulum as autophagic vesicles targeted for lysosomal degradation (18,19). This phenomenon appears to be substantiated by the observed overexpression of immunoglobulin heavy chain binding protein (BiP), a member of the heat-shock proteins 70 (HSP70) family of molecular chaperones, which binds avidly to misfolded proteins accumulated in the endoplasmic reticulum (20).…”