Endoplasmic reticulum stress in vasopressin neurons of familial diabetes insipidus model mice: aggregate formation and mRNA poly(A) tail shortening

Abstract

New findings r What is the topic of this review? Familial neurohypophysial diabetes insipidus (FNDI) is caused by a mutation in

The Novel Ser18del AVP Variant Causes Inherited Neurohypophyseal Diabetes Insipidus by Mechanisms Shared with Other Signal Peptide Variants

“…Interestingly, when using a human neuronal cell line (SH-SY5Y) and quantitative RT-PCR, we found a significant reduction in mRNA levels in cells expressing the Ser18del variant as well as the 3 other variants compared to the WT. Our findings could be explained by shortening of the AVP mRNA poly(A) tail due to ER stress, as described in a study using the Cys98Stop KI mouse model [14]. In that study, the authors suggest that AVP-expressing neurons are shortening the poly(A) tails, leading to a degradation of mRNA, which reduces the protein load to the ER, thereby preventing protein misfolding, stress, and intracellular retention.…”

“…As a first step, we aimed to examine whether the expression of AVP mRNA was affected. An effect on the mRNA level has previously been indicated for another adFNDI-associated AVP variant (Cys98Stop) when investigated in a KI mouse strain [14].…”

The hypothalamic–neurohypophysial system: genomes, genes and genetics

“…Thus, progressive polyuria in FNDI mice could proceed in the absence of VP neuronal cell death, in contrast to the autophagy described in a number of previous studies cited in this report. Arima et al (2014) suggest that the mechanism underlying decreased VP production in their FNDI mice is akin to processes involved in endoplasmic reticulum stress. They conclude that the shortening of Avp poly(A) length in FNDI mice may result in decreased Avp mRNA stability and decreased VP in FNDI mice or that the decreased VP poly(A) tail may be a cellular protective mechanism to diminish accumulated mutant VP.…”

“…The challenge will be to identify the major targets of these miRNAs; that some targets are undoubtedly important is evidenced by the fact that deletion of an enzyme, Dicer, essential for producing the mature form of miRNAs, in arcuate nuclei pro-opiomelanocortin neurones leads to obesity (Schneeberger et al 2013). It will also be interesting to see how hypothalamic nuclei miRNA expression profiles alter in response to changes in water or nutrient balance, which can be performed in parallel to compiling the expression profiles of coding mRNAs from the same cDNA library.Hiroshi Arima et al (2014) shift our attention to their findings on a mouse model of familial neurohypophysial diabetes insipidus (FNDI) and pose the question, how do these mice cope with an accumulation of unfolded or misfolded VP precursor in neurones? Familial neurohypophysial diabetes insipidus is characterized by poluria and polydipsia caused by a deficiency in VP production.…”

“…Hiroshi Arima et al (2014) shift our attention to their findings on a mouse model of familial neurohypophysial diabetes insipidus (FNDI) and pose the question, how do these mice cope with an accumulation of unfolded or misfolded VP precursor in neurones? Familial neurohypophysial diabetes insipidus is characterized by poluria and polydipsia caused by a deficiency in VP production.…”