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

2018 ◽  
Vol 682 ◽  
pp. 50-55 ◽  
Author(s):  
Masayoshi Tochiya ◽  
Daisuke Hagiwara ◽  
Yoshinori Azuma ◽  
Takashi Miyata ◽  
Yoshiaki Morishita ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Mouse Model ◽  
Diabetes Insipidus ◽  
Arginine Vasopressin ◽  
Mutant Protein ◽  
Protein Accumulation ◽  
Chemical Chaperone ◽  
Vasopressin Neurons

Activation of vasopressin neurons leads to phenotype progression in a mouse model for familial neurohypophysial diabetes insipidus

2010 ◽  
Vol 298 (2) ◽  
pp. R486-R493 ◽  
Author(s):  
Maiko Hiroi ◽  
Yoshiaki Morishita ◽  
Masayuki Hayashi ◽  
Nobuaki Ozaki ◽  
Yoshihisa Sugimura ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Mouse Model ◽  
Diabetes Insipidus ◽  
Inclusion Bodies ◽  
Autosomal Dominant ◽  
Urine Volume ◽  
Vehicle Control ◽  
Aggregate Formation ◽  
Vasopressin Neurons ◽  
Immunohistochemical Analyses

Familial neurohypophysial diabetes insipidus (FNDI) is a rare disease that is inherited in an autosomal dominant manner. In a previous study, we made a mouse model for FNDI, which showed progressive polyuria accompanied by inclusion bodies in the arginine vasopressin (AVP) neurons formed by aggregates in the endoplasmic reticulum. The present study was conducted to determine whether the activities of AVP neurons are related to the phenotype progression in the FNDI model. In the first experiment, female heterozygous mice were administered either desmopressin (dDAVP) or a vehicle (control) subcutaneously with osmotic minipumps for 30 days. The dDAVP treatment significantly decreased the urine volume, AVP mRNA expression, and inclusion bodies in the AVP neurons. Urine volume in the dDAVP group remained significantly less than the control for 14 days even after the minipumps were removed. In the second experiment, the males were fed either a 0.2% Na or 2.0% Na diet for 6 mo. Urine AVP excretion was significantly increased in the 2.0% Na group compared with the 0.2% Na group for the first 2 mo but gradually decreased thereafter. Throughout the experiments, urine volume increased progressively in the 2.0% Na group but not in the 0.2% Na group. Immunohistochemical analyses revealed that inclusion bodies in the AVP cells had significantly increased in the 2.0% Na compared with the 0.2% Na group. These data demonstrated that activation of AVP neurons could accelerate the aggregate formation as well as the progression of the polyuria in the FNDI model mice.

scholarly journals Transcriptomic Analysis Reveals that Atf3/c-Jun/Lgals3 axis is associated with Central Diabetes Insipidus after Hypothalamic Injury

2021 ◽  
Author(s):  
Mingfeng Zhou ◽  
Yichao Ou ◽  
Guangsen Wu ◽  
Kai Li ◽  
Junjie Peng ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Arginine Vasopressin ◽  
Body Fluid ◽  
Microglial Activation ◽  
The Body ◽  
Transcriptomic Analysis ◽  
Central Diabetes Insipidus ◽  
Electrolyte Imbalance ◽  
Hypothalamic Injury ◽  
Vasopressin Neurons

Background: Hypothalamic injury causes several complicated neuroendocrine-associated disorders, such as water-electrolyte imbalance, obesity, and hypopituitarism. Among these, central diabetes insipidus (CDI), characterized by polyuria, polydipsia, low urine specific gravity, and deficiency of arginine vasopressin contents, is a typical complication after hypothalamic injury. Methods: CDI was induced by hypothalamic pituitary stalk injury in male animals. Behavioral parameters and blood sample were collected to evaluate the characteristics of body fluid metabolism imbalance. The brains were harvested for high-throughput RNA sequencing and immunostaining to identify pathophysiological changes in corresponding hypothalamic nuclei. Results: Based on transcriptomic analysis, we demonstrated the upregulation of the Atf3/c-Jun axis and identified Lgals3, a microglial activation related gene, as the most significant target gene in response to the body fluid imbalance in CDI. Furthermore, we found that the microglia possessed elevated phagocytic ability, which could promote the elimination of arginine vasopressin neurons after hypothalamic injury. Conclusion: Our findings suggested that the Atf3/c-Jun/Lgals3 axis was associated with the microglial activation, and might participate in the loss of functional arginine vasopressin neurons in CDI after hypothalamic injury.

scholarly journals Degradation of Mutant Protein Aggregates within the Endoplasmic Reticulum of Vasopressin Neurons

iScience ◽  
2020 ◽  
Vol 23 (10) ◽  
pp. 101648
Author(s):  
Takashi Miyata ◽  
Daisuke Hagiwara ◽  
Yuichi Hodai ◽  
Tsutomu Miwata ◽  
Yohei Kawaguchi ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Aggregates ◽  
Mutant Protein ◽  
Vasopressin Neurons

scholarly journals Differential Cellular Handling of Defective Arginine Vasopressin (AVP) Prohormones in Cells Expressing Mutations of the AVP Gene Associated with Autosomal Dominant and Recessive Familial Neurohypophyseal Diabetes Insipidus

2004 ◽  
Vol 89 (9) ◽  
pp. 4521-4531 ◽  
Author(s):  
Jane H. Christensen ◽  
Charlotte Siggaard ◽  
Thomas J. Corydon ◽  
Gary L. Robertson ◽  
Niels Gregersen ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Amino Acid ◽  
Diabetes Insipidus ◽  
Arginine Vasopressin ◽  
Autosomal Dominant ◽  
Autosomal Dominant Inheritance ◽  
Laser Scanning Microscopy ◽  
Recessive Mutation ◽  
Dominant Inheritance ◽  
Avp Gene

An unusual mutation in the arginine vasopressin (AVP) gene, predicting a P26L amino acid substitution of the AVP prohormone, is associated with autosomal recessive familial neurohypophyseal diabetes insipidus (FNDI). To investigate whether the cellular handling of the P26L prohormone differed from that of the Y21H prohormone associated with autosomal dominant inheritance of FNDI, the mutations were examined by heterologous expression in cell lines. Immunoprecipitation demonstrated retarded processing and secretion of the Y21H prohormone, whereas the secretion of the P26L prohormone seemed to be unaffected. Confocal laser scanning microscopy showed accumulation of the Y21H prohormone in the endoplasmic reticulum, whereas the P26L prohormone and/or processed products were localized in secretory granules in the cellular processes. RIA analysis showed reduced amounts of immunoreactive Y21H-AVP and P26L-AVP in the cell culture medium. Thus, the recessive mutation does not seem to affect the intracellular trafficking but rather the final processing of the prohormone. Our results provide an important negative control in support of the hypothesis that autosomal dominant inheritance of FNDI is caused by mutations in the AVP gene that alter amino acid residues important for folding and/or dimerization of the neurophysin II moiety of the AVP prohormone and subsequent transport from the endoplasmic reticulum.

scholarly journals Endoplasmic reticulum chaperone BiP/GRP78 knockdown leads to autophagy and cell death of arginine vasopressin neurons in mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yohei Kawaguchi ◽  
Daisuke Hagiwara ◽  
Takashi Miyata ◽  
Yuichi Hodai ◽  
Junki Kurimoto ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Arginine Vasopressin ◽  
Urine Volume ◽  
Neuronal Loss ◽  
Protective Role ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Vasopressin Neurons

AbstractThe immunoglobulin heavy chain binding protein (BiP), also referred to as 78-kDa glucose-regulated protein (GRP78), is a pivotal endoplasmic reticulum (ER) chaperone which modulates the unfolded protein response under ER stress. Our previous studies showed that BiP is expressed in arginine vasopressin (AVP) neurons under non-stress conditions and that BiP expression is upregulated in proportion to the increased AVP expression under dehydration. To clarify the role of BiP in AVP neurons, we used a viral approach in combination with shRNA interference for BiP knockdown in mouse AVP neurons. Injection of a recombinant adeno-associated virus equipped with a mouse AVP promoter and BiP shRNA cassette provided specific BiP knockdown in AVP neurons of the supraoptic (SON) and paraventricular nuclei (PVN) in mice. AVP neuron-specific BiP knockdown led to ER stress and AVP neuronal loss in the SON and PVN, resulting in increased urine volume due to lack of AVP secretion. Immunoelectron microscopy of AVP neurons revealed that autophagy was activated through the process of AVP neuronal loss, whereas no obvious features characteristic of apoptosis were observed. Pharmacological inhibition of autophagy by chloroquine exacerbated the AVP neuronal loss due to BiP knockdown, indicating a protective role of autophagy in AVP neurons under ER stress. In summary, our results demonstrate that BiP is essential for the AVP neuron system.

scholarly journals Arginine vasopressin neuronal loss results from autophagy-associated cell death in a mouse model for familial neurohypophysial diabetes insipidus

2014 ◽  
Vol 5 (3) ◽  
pp. e1148-e1148 ◽  
Author(s):  
D Hagiwara ◽  
H Arima ◽  
Y Morishita ◽  
L Wenjun ◽  
Y Azuma ◽  
...  
Keyword(s):  
Cell Death ◽  
Mouse Model ◽  
Diabetes Insipidus ◽  
Arginine Vasopressin ◽  
Neuronal Loss

scholarly journals Chemical Chaperones Reduce Endoplasmic Reticulum Stress and Prevent Mutant HFE Aggregate Formation

2007 ◽  
Vol 282 (38) ◽  
pp. 27905-27912 ◽  
Author(s):  
Sérgio F. de Almeida ◽  
Gonçalo Picarote ◽  
John V. Fleming ◽  
Maria Carmo-Fonseca ◽  
Jorge E. Azevedo ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Molecular Mechanisms ◽  
Hereditary Hemochromatosis ◽  
Signal Transduction Pathway ◽  
Mutant Protein ◽  
Chemical Chaperone ◽  
Chemical Chaperones ◽  
Unfolded Protein ◽  
The Stability ◽  
Intracellular Aggregates

HFE C282Y, the mutant protein associated with hereditary hemochromatosis (HH), fails to acquire the correct conformation in the endoplasmic reticulum (ER) and is targeted for degradation. We have recently shown that an active unfolded protein response (UPR) is present in the cells of patients with HH. Now, by using HEK 293T cells, we demonstrate that the stability of HFE C282Y is influenced by the UPR signaling pathway that promotes its degradation. Treatment of HFE C282Y-expressing cells with tauroursodeoxycholic acid (TUDCA), a bile acid derivative with chaperone properties, or with the chemical chaperone sodium 4-phenylbutyrate (4PBA) impeded the UPR activation. However, although TUDCA led to an increased stability of the mutant protein, 4PBA contributed to a more efficient disposal of HFE C282Y to the degradation route. Fluorescence microscopy and biochemical analysis of the subcellular localization of HFE revealed that a major portion of the C282Y mutant protein forms intracellular aggregates. Although neither TUDCA nor 4PBA restored the correct folding and intracellular trafficking of HFE C282Y, 4PBA prevented its aggregation. These data suggest that TUDCA hampers the UPR activation by acting directly on its signal transduction pathway, whereas 4PBA suppresses ER stress by chemically enhancing the ER capacity to cope with the expression of misfolded HFE, facilitating its degradation. Together, these data shed light on the molecular mechanisms involved in HFE C282Y-related HH and open new perspectives on the use of orally active chemical chaperones as a therapeutic approach for HH.

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