☆ 4.7 Article

Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the UPR in models of neurodegeneration

MOLECULAR THERAPY (2021)

Journal

MOLECULAR THERAPY

Volume 29, Issue 5, Pages 1862-1882

Publisher

CELL PRESS

DOI: 10.1016/j.ymthe.2021.01.033

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Funding

FONDEF [ID16I10223, D11E1007]
FONDECYT [1181089, 1180186, 3150097, 1191003]
FONDAP [15150012]
Millenium Institute [P09-015-F]
CONICYT-Brazil [441921/2016-7]
US Air Force Office of Scientific Research [FA9550-16-10384]
US Office of Naval Research-Global (ONR-G) [N62909-16-1-2003]
CONICYT PhD fellowship [21160843]
Programa de Apoyo a Centros con Financiamiento Basal [AFB-170004]
NIH [NS092829, AG046495]

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Abstract

The fusion protein UPRplus, combining ATF6f and XBP1s, shows stronger effects in reducing abnormal protein aggregation compared to XBP1s or ATF6 alone. Delivery of UPRplus into the brain using adeno-associated viruses demonstrates potent neuroprotection in preclinical models of Parkinson's and Huntington's disease. Directing UPR-mediated gene expression towards specific adaptive programs may serve as a strategy to optimize the beneficial effects of the pathway in different disease conditions.

Alteration to endoplasmic reticulum (ER) proteostasis is observed in a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteostasis and cell function. The UPR is initiated by specialized stress sensors that engage gene expression programs through the concerted action of the transcription factors ATF4, ATF6f, and XBP1s. Although UPR signaling is generally studied as unique linear signaling branches, correlative evidence suggests that ATF6f and XBP1s may physically interact to regulate a subset of UPR target genes. In this study, we designed an ATF6f/XBP1s fusion protein termed UPRplus that behaves as a heterodimer in terms of its selective transcriptional activity. Cell-based studies demonstrated that UPRplus has a stronger effect in reducing the abnormal aggregation of mutant huntingtin and a-synuclein when compared to XBP1s or ATF6 alone. We developed a gene transfer approach to deliver UPRplus into the brain using adeno-associated viruses (AAVs) and demonstrated potent neuroprotection in vivo in preclinical models of Parkinson's disease and Huntington's disease. These results support the concept in which directing UPR-mediated gene expression toward specific adaptive programs may serve as a possible strategy to optimize the beneficial effects of the pathway in different disease conditions.

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Deciphering the Link Between ERUPR Signaling and MicroRNA in Pathogenesis of Alzheimer's Disease

Nusrath Yasmeen, Manali Datta, Vikram Kumar, Fahad S. Alshehri, Atiah H. Almalki, Shafiul Haque

Summary: This article reviews the role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in the pathology of Alzheimer's disease (AD). By analyzing original research and review articles, the authors summarize the correlation between ERUPR signaling and miRNA dysregulation, as well as the involvement of adaptive UPR and apoptotic UPR in restoring protein homeostasis and triggering cell death.

FRONTIERS IN AGING NEUROSCIENCE (2022)