Neurohypophyseal diabetes insipidus (NDI) – which is characterised by excessive thirst and urination – results from mutations in the precursor of vasopressin, an antidiuretic hormone. In individuals with NDI, mutant pro-vasopressin accumulates in the ER of vasopressinergic neurons, causing cell death; however, the basis of this neurotoxicity has remained unclear. Now, Jonas Rutishauser and colleagues () shed light on how mutant pro-vasopressin is packaged in the ER. The authors study several disease-associated dominant mutant forms of pro-vasopressin, and show that the proteins form disulfide-linked homo-oligomeric aggregates both in fibroblasts and a neuronal cell line. The aggregates are visible by immunofluorescence and immunogold EM, and colocalise with the ER chaperone calreticulin. On the basis of mutagenesis experiments, the authors conclude that no specific single cysteine is essential for aggregation in vivo, although the presence of cysteines is required. Notably, the aggregates have a fibrillar substructure, and purified recombinant pro-vasopressin mutants spontaneously form fibrils in vitro. On the basis of these data, the authors propose that autosomal dominant NDI – similar to other neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease – is associated with the formation of fibrillar protein aggregates.
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