Formation of Endoplasmic Reticulum-Associated Compartment in Vasopressin Neurons: A Mechanism by Which Endoplasmic Reticulum Stress is Reduced

Analyses of a mouse model for familial neurohypophysial diabetes insipidus (FNDI), a disease characterized by progressive polyuria due to progressive decreases in arginine vasopressin (AVP) release, revealed that mutant proteins are accumulated in a sub-compartment of the endoplasmic reticulum (ER) of AVP neurons. By forming such a structure called ER-associated compartment (ERAC), AVP neurons are likely to reduce ER stress. However, the formation of ERAC is hampered in FNDI mice which are relatively old or subjected to chronic dehydration. Failure of ERAC formation induces autophagy in AVP neurons, which are finally lost through autophagy-associated cell death. It is also worthwhile that enlargement of a sub-compartment of ER, a structure similar to ERAC, was observed in the AVP neurons in wild-type mice subjected to dehydration. Activating transcription factor 6 (ATF6 ), one of three ER stress sensors, contributes to the formation of ERAC, as the ER was dilated diffusely in AVP neurons of dehydrated ATF6 knockout mice. Thus, our data suggest that misfolded proteins are sensed via ER stress sensors including ATF6 , and confined to the ERAC in AVP neurons. This mechanism seems to apply to the AVP neurons of not only FNDI but also wild-type mice.