Chemical chaperone 4-phenylbutylate reduces mutant protein accumulation in the endoplasmic reticulum of arginine vasopressin neurons in a mouse model for familial neurohypophysial diabetes insipidus. (24th August 2018)

• Record Type: Journal Article
• Authors: Tochiya, Masayoshi; Hagiwara, Daisuke; Azuma, Yoshinori; Miyata, Takashi; Morishita, Yoshiaki; Suga, Hidetaka; Onoue, Takeshi; Tsunekawa, Taku; Takagi, Hiroshi; Ito, Yoshihiro; Iwama, Shintaro; Goto, Motomitsu; Banno, Ryoichi; Arima, Hiroshi
• Is Part Of: Neuroscience letters. Volume 682(2018)
• Page Start: 50
• Page End: 55
• Publication Date: 2018-08-24
• Subjects: FNDI familial neurohypophysial diabetes insipidus -- AVP arginine vasopressin -- ER endoplasmic reticulum -- 4-PBA 4-phenylbutylate -- SON supraoptic nucleus -- PVN paraventricular nucleus -- NPII neurophysin II -- ERAC endoplasmic reticulum-associated compartment -- BiP immunoglobulin heavy chain binding protein -- PFA paraformaldehyde -- SCN suprachiasmatic nucleus -- NIH National Institutes of Health -- AU arbitrary units; Familial neurohypophysial diabetes insipidus (FNDI) -- 4-Phenylbutylate (4-PBA) -- Endoplasmic reticulum (ER) stress -- Endoplasmic reticulum-associated compartment (ERAC) -- Arginine vasopressin (AVP); Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2018.06.013
• Languages: English
• ISSNs: 0304-3940

Abstract

Highlights: We examined therapeutic effects of the chemical chaperone 4-PBA in FNDI mice. 4-PBA ameliorated accumulation of mutant AVP precursors in the ER of AVP neurons. 4-PBA attenuated polyuria and AVP neuron loss in FNDI mice. Abstract: Familial neurohypophysial diabetes insipidus (FNDI), characterized by progressive polyuria and loss of arginine vasopressin (AVP) neurons, is an autosomal dominant disorder caused by AVP gene mutations. Our previous studies with FNDI model mice demonstrated that mutant proteins accumulated in the endoplasmic reticulum (ER) of AVP neurons. Here, we examined therapeutic effects of the chemical chaperone 4-phenylbutylate (4-PBA) in FNDI mice. Treatment with 4-PBA reduced mutant protein accumulation in the ER of FNDI mice and increased AVP release, leading to reduced urine volumes. Furthermore, AVP neuron loss under salt loading was attenuated by 4-PBA treatment. These data suggest that 4-PBA ameliorated mutant protein accumulation in the ER of AVP neurons and thereby prevented FNDI phenotype progression.