The peptide hormone vasopressin, which regulates water homeostasis in the kidney, is synthesized into the endoplasmic reticulum (ER) of hypothalamic neurons as a prohormone consisting of the nonapeptide hormone, the carrier protein neurophysin II, and a 39 amino-acid glycopeptide. In the trans-Golgi it is sorted as an aggregate into secretory granules and cleaved into its three moieties. Heterozygous mutations in provasopressin cause autosomal dominant neurohypophyseal diabetes insipidus (ADNDI), a dominant disease resulting in the loss of vasopressinergic neurons. When expressed in transfected cells, the mutant precursor is retained in the ER and forms fibrillar aggregates.

We aim to define the minimal requirements for amyloid aggregation and cytotoxicity of provasopressin mutants and to study the cell’s response to pathogenic mutants.  Our experiments will help elucidate the pathomechanisms of ADNDI in the context of intracellular accumulation of mutant protein, which is a hallmark of neurodegeneration.

In light of recent findings that the secretory granules represent physiological amyloids, ADNDI may be the result of premature, mislocalized and therefore pathological aggregation.