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First published online November 4, 2009

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Forming fibrils in the ER

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 (p. 3994) 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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Related articles in JCS:

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

Julia Birk, Michael A. Friberg, Cristina Prescianotto-Baschong, Martin Spiess, and Jonas Rutishauser
JCS 2009 122: 3994-4002. [Abstract] [Full Text]  

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JCS Similar articles in this journal Alert me to new issues of the journal Download to citation manager Social Bookmarking                         What's this?