Herp Reduces ER Calcium Content by Proteasomal Degradation of SERCA

Herp, an endoplasmic reticulum (ER) stress inducible protein, reduces ER Ca2+ content in neurons and prevents their apoptosis. An understanding of the mechanism by which Herp decreases ER Ca2+ content requires studies of Herp interacting proteins, which could be SERCA and the proteasome. Herp may recruit the proteasome from the cytosol to the ER membrane, thereby facilitating the ER associated degradation (ERAD) of SERCA. The proteasome recruitment and the subsequent degradation of SERCA reduce ER lumenal Ca2+ concentration and the Ca2+ release during ER stress which counteracts the activation of apoptosis. This proposal describes how to determine the mechanism through which Herp reduces ER Ca2+ content, how to test the proteasomal degradation of SERCA, how to illustrate the proteasome recruitment to the ER membrane, and how to demonstrate the interaction between Herp and SERCA. The work will provide a new regulatory link between ER stress and Ca2+ homeostasis. In addition, studies of the proteasomal degradation of SERCA will broaden our present understanding of the regulation of SERCA. Since dysregulation of Ca2+ homeostasis has been implicated in the pathophysiology of several neurodegenerative diseases like Alzheimer's and Huntington's, research focused on Herp may lead to insights regarding therapies for those.