Amyloid-β42 clearance and neuroprotection mediated by X-box binding protein 1 signaling decline with aging in the Drosophila brain

Authors
Marcora, Maria Silvina; Belfiori Carrasco, Lautaro F.; Bocai, Nadia Irina; Morelli, Laura; Castaño, Eduardo Miguel
Publication Year
2017
Language
English
Format
article
Status
Published version
Description
The unfolded protein response (UPR) may be pathogenically related to Alzheimer's disease. Yet, the effects of chronic amyloid-β42 (Aβ42) accumulation and UPR activation upon neurotoxicity remain unclear. Here, we show that neuronal Aβ42 expression in Drosophila activated the inositol-requiring protein-1/X-box binding protein 1 (XBP1) UPR branch before the onset of behavioral impairment and persisted with aging. Early upregulation of hsc3/BiP, a target of XBP1 and activating transcription factor 6 pathways, was also sustained in old animals. Downregulation of XBP1 enhanced neurotoxicity and the accumulation of Aβ42 and polyubiquitinated proteins. Consistently, overexpression of spliced XBP1 reduced Aβ42 and improved geotaxis in old flies. The activation of protein kinase RNA-like endoplasmic reticulum (ER) kinase contributed to the age-dependent geotaxis deficit. Spliced XBP1 gene targets ER degradation-enhancing mannosidase-like protein 1, ER degradation-enhancing mannosidase-like protein 2, and HRD1 were elevated in 5-day-old Aβ42-expressing flies as compared to controls but not in 18-day-old flies. Our results indicate that inositol-requiring protein-1/XBP1 activation is neuroprotective and enhances Aβ42 clearance. They also suggest that such response becomes inefficient with aging.
Fil: Marcora, Maria Silvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Belfiori Carrasco, Lautaro F.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Bocai, Nadia Irina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Castaño, Eduardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Subject
ALZHEIMER'S DISEASE
AMYLOID Β
DROSOPHILA
NEURODEGENERATION
UNFOLDED PROTEIN RESPONSE
XBP1
Inmunología
Medicina Básica
CIENCIAS MÉDICAS Y DE LA SALUD
Access level
Restricted access
License
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repository
CONICET Digital (CONICET)
Institution
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identifier
oai:ri.conicet.gov.ar:11336/37290