Endoplasmic Reticulum Stress-inducible Protein, Herp, Enhances Presenilin-mediated Generation of Amyloid β-Protein

Abstract

Presenilin (PS) is essential for the ␥-cleavage required for the generation of the C terminus of amyloid ␤-protein (A␤). However, the mechanism underlying PS-mediated ␥-cleavage remains unclear. We have identified Herp cDNA by our newly developed screening method for the isolation of cDNAs that increase the degree of ␥-cleavage. Herp was originally identified as a homocysteine-responsive protein, and its expression is up-regulated by endoplasmic reticulum stress. Herp is an endoplasmic reticulum-localized membrane protein that has a ubiquitin-like domain. Here, we report that a high expression of Herp in cells increases the level of A␤ generation, although not in PS-deficient cells. We found that Herp interacts with both PS1 and PS2. Thus, Herp regulates PS-mediated A␤ generation, possibly through its binding to PS. Immunohistochemical analysis of a normal human brain section with an anti-Herp antibody revealed the exclusive staining of neurons and vascular smooth muscle cells. Moreover, the antibody strongly stained activated microglia in senile plaques in the brain of patients with Alzheimer disease. Taken together, Herp could be involved in A␤ accumulation, including the formation of senile plaques and vascular A␤ deposits.

Herp Stabilizes Neuronal Ca2+ Homeostasis and Mitochondrial Function during Endoplasmic Reticulum Stress

“…The function of Herp is unknown. Sai et al (14) showed that Herp binds to PS1 and alters APP processing in HEK-293 cells, although it is not known whether the interaction affects the PS1 role in regulating ER Ca 2ϩ homeostasis, which might also contribute to altered APP processing in neurons (15). In the present study we demonstrate a role for Herp in stabilizing cellular Ca 2ϩ homeostasis and preventing neuronal death following ER stress.…”

“…A recent study by Sai et al (14) showed that Herp physically interacts with PS1, an ER integral membrane protein that has been linked to APP metabolism, ER Ca 2ϩ regulation, and apoptosis (6). The contribution of this interaction to ER Ca 2ϩ homeostasis may be dependent on the expression of APP as its processed carboxyl APP derivatives have been shown to regulate the expression of genes involved in ER Ca 2ϩ homeostasis (58).…”

“…In this study, we did not examine levels of the APP derivatives nor their downstream nuclear signaling activities (59). Clearly, further insight into Herp function will emerge from a better understanding of its interaction with PS1 and other ER resident proteins and how these interactions affect ER Ca 2ϩ homeostasis and downstream cellular Ca 2ϩ signaling that has been shown to impact APP processing (14,15) and neuronal vulnerability to ER stress (11). PS1 mutations that cause AD perturb ER Ca 2ϩ regulation in a manner that results in overfilling of ER Ca 2ϩ stores (11,12).…”

Whole genome expression profiling of the medial and lateral substantia nigra in Parkinson’s disease

“…It is well known that the accumulation of misfolded proteins in ER triggers an "unfolded protein response" (UPR), which increases transcription of genes encoding for ER chaperones and enzymes associated with ER protein degradation [25]. In the normal brain HERPUD1 has been localised to neurones, and it is found in activated microglia in senile plaques in the brains of Alzheimer's disease patients [26]. A microarray study of a 6-hydroxydopamine (6-OHDA)-treated dopaminergic cell line also shows that the neurotoxin stimulates pathways associated with cellular stress and the UPR accompanied by the expression of HERPUD1 [27].…”

A Monoclonal Antibody against Human Homocysteine-Induced Endoplasmic Reticulum Protein (Herp): A Useful Tool for Evaluating Endoplasmic Reticulum Stress

“…High expression of Herp with formation of amyloid β -protein deposited in vascular cells was observed in the brains of patients with Alzheimer disease (Sai et al 2002). Herp may regulate neuronal Ca 2+ signaling (Chan et al 2004), and the expression of Herp markedly increased in neurons of rats subjected to ER stress (Hori et al 2004).…”