Involvement of Gadd153 in the pathogenic action of presenilin‐1 mutations

Abstract

Mutations in the presenilin-1 (PS1) gene cause early onset familial Alzheimer's disease (FAD) by a mechanism believed to involve perturbed endoplasmic reticulum (ER) function and altered proteolytic processing of the amyloid precursor protein. We investigated the molecular mechanisms underlying cell death and ER dysfunction in cultured cells and knock-in mice expressing FAD PS1 mutations. We report that PS1 mutations cause a marked increase in basal protein levels of the pro-apoptotic transcription factor Gadd153. PS1 mutations increase Gadd153 protein translation without affecting mRNA levels, while decreasing levels of the anti-apoptotic protein Bcl-2. Moreover, an exaggerated Gadd153 response to stress induced by ER stress agents was observed in PS1 mutant cells. Cell death in response to ER stress is enhanced by PS1 mutations, and this endangering effect is attenuated by antisense-mediated suppression of Gadd153 production. An abnormality in the translational regulation of Gadd153 may sensitize cells to the detrimental effects of ER stress and contribute to the pathogenic actions of PS1 mutations in FAD.

Ghrelin suppresses tunicamycin- or thapsigargin-triggered endoplasmic reticulum stress-mediated apoptosis in primary cultured rat cortical neuronal cells

“…Specifically, mRNA and protein levels of CHOP were increased in the hippocampus after occlusion of common carotid arteries whereas ischemia-induced neuronal cell death was decreased in CHOP knockout mice [15]. Mutations in the presenilin-1 gene cause a marked increase in CHOP protein, and this hazardous effect is attenuated by anti-sense-mediated suppression of CHOP production [48]. CHOP expression was dramatically increased by the Parkinsonism-inducing neurotoxin 6-hydroxydopamine in neurons [49,50].…”

Roles of CHOP/GADD153 in endoplasmic reticulum stress

“…97 However, concerning the role of presenilin-1 in the ER stress pathway, the question of whether or not presenilin-1 mutations downregulate induction of BiP and CHOP is still being debated. 98,99 Therefore, it remains to be studied whether CHOP induction and ER stress-mediated apoptosis occur in the development of Alzheimer's disease. Several studies indicate that oxidative damages may have an important role in the development of Parkinson's disease.…”

Mitochondrial Dysfunction, Endoplasmic Reticulum Stress, and Apoptosis in Alzheimer’s Disease

“…Ab fragment 25 -35 (Ab [25][26][27][28][29][30][31][32][33][34][35] ) and Ab 1-42 cause a loss of mitochondrial membrane potential by activating NADPH oxidase, as well as metabolic pathways upstream of mitochondrial respiration, in astrocytes (13). Ab [25][26][27][28][29][30][31][32][33][34][35] inhibits respiratory complex I and decreases cellular ATP content of both astrocytes and neurons (14). Ab [25][26][27][28][29][30][31][32][33][34][35] induces translocation of the second-mitochondriaderived activator of caspase (Smac) from mitochondria to cytosol via AP-1 / Bim activation (15).…”