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First published online 13 October 2009
doi: 10.1242/jcs.051136

Journal of Cell Science 122, 3994-4002 (2009)
Published by The Company of Biologists 2009
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Research Article

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{ddagger} and Jonas Rutishauser{ddagger},§

Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland

§ Author for correspondence (j.rutishauser{at}unibas.ch)

Accepted 21 August 2009

Autosomal dominant neurohypophyseal diabetes insipidus results from mutations in the precursor protein of the antidiuretic hormone arginine vasopressin. Mutant prohormone is retained in the endoplasmic reticulum of vasopressinergic neurons and causes their progressive degeneration by an unknown mechanism. Here, we show that several dominant pro-vasopressin mutants form disulfide-linked homo-oligomers and develop large aggregations visible by immunofluorescence and immunogold electron microscopy, both in a fibroblast and a neuronal cell line. Double-labeling showed the pro-vasopressin aggregates to colocalize with the chaperone calreticulin, indicating that they originated from the endoplasmic reticulum. The aggregates revealed a remarkable fibrillar substructure. Bacterially expressed and purified mutant pro-vasopressin spontaneously formed fibrils under oxidizing conditions. Mutagenesis experiments showed that the presence of cysteines, but no specific single cysteine, is essential for disulfide oligomerization and aggregation in vivo. Our findings assign autosomal dominant diabetes insipidus to the group of neurodegenerative diseases associated with the formation of fibrillar protein aggregates.

Key words: Aggregates, Diabetes insipidus, Fibrils, Neurophysin, Vasopressin


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