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

Marcora, María Silvina; Belfiori-Carrasco, Lautaro F.; Bocai, Nadia I.; Morelli, Laura; Castaño, Eduardo M.

doi:10.1016/j.neurobiolaging.2017.08.012

Cited by 22 publications

(22 citation statements)

References 80 publications

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“…For tau-exacerbated aging (right panel), all simulated deficiencies, including the UPR mt , caused a decrease in cell survival, suggesting all of these pathways are critical in mitigating tau-dependent damage in aging nervous systems. This is especially consistent with findings that display the profound ameliorative effects of daf-16/FOXO activation, specific UPR ER activation and regulation, UPR mt activation and mitophagy on proteotoxic AD models of neurodegeneration (Chen et al, 2015;Marcora et al, 2017;Sorrentino et al, 2017;Fang et al, 2019). It is speculated here that all of these responses must act in concert to maintain resilient neuronal phenotypes, but the agedependent deterioration of these quality control processes is yet to be fully understood.…”

Section: Neuronal Survival During Aging Depends On Multiple Stress Response Pathwayssupporting

confidence: 89%

Network Simulations Reveal Molecular Signatures of Vulnerability to Age-Dependent Stress and Tau Accumulation

Hoffman

Hanneman

Moreno

2020

Front. Mol. Biosci.

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Alzheimer's disease (AD) is the leading cause of dementia and one of the most common causes of death worldwide. As an age-dependent multifactorial disease, the causative triggers of AD are rooted in spontaneous declines in cellular function and metabolic capacity with increases in protein stressors such as the tau protein. This multitude of age-related processes that cause neurons to change from healthy states to ones vulnerable to the damage seen in AD are difficult to simultaneously investigate and even more difficult to quantify. Here we aimed to diminish these gaps in our understanding of neuronal vulnerability in AD development by using simulation methods to theoretically quantify an array of cellular stress responses and signaling molecules. This temporally-descriptive molecular signature was produced using a novel multimethod simulation approach pioneered by our laboratory for biological research; this methodology combines hierarchical agent-based processes and continuous equation-based modeling in the same interface, all while maintaining intrinsic distributions that emulate natural biological stochasticity. The molecular signature was validated for a normal organismal aging trajectory using experimental longitudinal data from Caenorhabditis elegans and rodent studies. In addition, we have further predicted this aging molecular signature for cells impacted by the pathogenic tau protein, giving rise to distinct stress response conditions needed for cytoprotective aging. Interestingly, our simulation experiments showed that oxidative stress signaling (via daf-16 and skn-1 activities) does not substantially protect cells from all the early stressors of aging, but that it is essential in preventing a late-life degenerative cellular phenotype. Together, our simulation experiments aid in elucidating neurodegenerative triggers in the onset of AD for different genetic conditions. The long-term goal of this work is to provide more detailed diagnostic and prognostic tools for AD development and progression, and to provide more comprehensive preventative measures for this disease.

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Section: Neuronal Survival During Aging Depends On Multiple Stress Response Pathwayssupporting

confidence: 89%

Network Simulations Reveal Molecular Signatures of Vulnerability to Age-Dependent Stress and Tau Accumulation

Hoffman

Hanneman

Moreno

2020

Front. Mol. Biosci.

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“…Many proteins in the UPR pathway have been linked to neurodegenerative diseases. For example, x-box protein 1 (XBP1) has been found to be neuroprotective in Drosophila expressing amyloid-β42 in neurons (Marcora et al, 2017). XBP1 is a downstream effector of IRE1, one of the triggers that initiates part of the UPR cascade upon sensing unfolded protein buildup in the ER (Wei et al, 2015).…”

Section: Protein Synthesis Linked To Neurological Diseasementioning

confidence: 99%

Homeostatic Roles of the Proteostasis Network in Dendrites

Lottes

Cox

2020

Front. Cell. Neurosci.

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Cellular protein homeostasis, or proteostasis, is indispensable to the survival and function of all cells. Distinct from other cell types, neurons are long-lived, exhibiting architecturally complex and diverse multipolar projection morphologies that can span great distances. These properties present unique demands on proteostatic machinery to dynamically regulate the neuronal proteome in both space and time. Proteostasis is regulated by a distributed network of cellular processes, the proteostasis network (PN), which ensures precise control of protein synthesis, native conformational folding and maintenance, and protein turnover and degradation, collectively safeguarding proteome integrity both under homeostatic conditions and in the contexts of cellular stress, aging, and disease. Dendrites are equipped with distributed cellular machinery for protein synthesis and turnover, including dendritically trafficked ribosomes, chaperones, and autophagosomes. The PN can be subdivided into an adaptive network of three major functional pathways that synergistically govern protein quality control through the action of (1) protein synthesis machinery; (2) maintenance mechanisms including molecular chaperones involved in protein folding; and (3) degradative pathways (e.g., Ubiquitin-Proteasome System (UPS), endolysosomal pathway, and autophagy. Perturbations in any of the three arms of proteostasis can have dramatic effects on neurons, especially on their dendrites, which require tightly controlled homeostasis for proper development and maintenance. Moreover, the critical importance of the PN as a cell surveillance system against protein dyshomeostasis has been highlighted by extensive work demonstrating that the aggregation and/or failure to clear aggregated proteins figures centrally in many neurological disorders. While these studies demonstrate the relevance of derangements in proteostasis to human neurological disease, here we mainly review recent literature on homeostatic developmental roles the PN machinery plays in the establishment, maintenance, and plasticity of stable and dynamic dendritic arbors. Beyond basic housekeeping functions, we consider roles of PN machinery in protein quality control mechanisms linked to dendritic plasticity (e.g., dendritic spine remodeling during LTP); cell-type specificity; dendritic morphogenesis; and dendritic pruning.

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“…Expression of XBP1 is also promoted by Aβ42, and overexpression of spliced XBP1 (XBP1-S), the activated form of XBP1, reduces Aβ42 toxicity in Drosophila photoreceptors, whereas knockdown of endogenous XBP1 intensifies rough eye phenotype induced by Aβ42 [35]. Moreover, a recent study showed that overexpression of XBP1-S in the fly brain reduces Aβ42 levels and improves Aβ42-induced locomotor dysfunction, while reduction of endogenous XBP1 increases Aβ42 protein levels and enhances Aβ42-induced locomotor dysfunction [124]. Furthermore, chronic expression of Aβ42 activates protein kinase R-like endoplasmic reticulum kinase (PERK) and ATF6 pathways, both major branches of the unfolded protein response, as well as inositol-requiring enzyme 1 α-XBP1 pathway, and Aβ42-induced activation of PERK may have a beneficial effect on AD by Aβ42 clearance [124].…”

Section: Endoplasmic Reticulum Stressmentioning

confidence: 99%

Genetic Dissection of Alzheimer’s Disease Using Drosophila Models

Jeon

Lee

Choi

et al. 2020

IJMS

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Alzheimer’s disease (AD), a main cause of dementia, is the most common neurodegenerative disease that is related to abnormal accumulation of the amyloid β (Aβ) protein. Despite decades of intensive research, the mechanisms underlying AD remain elusive, and the only available treatment remains symptomatic. Molecular understanding of the pathogenesis and progression of AD is necessary to develop disease-modifying treatment. Drosophila, as the most advanced genetic model, has been used to explore the molecular mechanisms of AD in the last few decades. Here, we introduce Drosophila AD models based on human Aβ and summarize the results of their genetic dissection. We also discuss the utility of functional genomics using the Drosophila system in the search for AD-associated molecular mechanisms in the post-genomic era.

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

Cited by 22 publications

References 80 publications

Network Simulations Reveal Molecular Signatures of Vulnerability to Age-Dependent Stress and Tau Accumulation

Network Simulations Reveal Molecular Signatures of Vulnerability to Age-Dependent Stress and Tau Accumulation

Homeostatic Roles of the Proteostasis Network in Dendrites

Genetic Dissection of Alzheimer’s Disease Using Drosophila Models

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