ER Proteostasis Control of Neuronal Physiology and Synaptic Function

Martínez, Gabriela; Khatiwada, Sanjeev; Costa-Mattioli, Mauro; Hetz, Claudio

doi:10.1016/j.tins.2018.05.009

Cited by 91 publications

(96 citation statements)

References 130 publications

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“…Surprisingly, overexpression of XBP1s in the hippocampus did not result in clear upregulation of canonical UPR target genes described in other tissues. This is in agreement with recent findings suggesting that the UPR, and more specifically XBP1, has alternative functions in the nervous system, directly controlling synaptic plasticity (32). Importantly, the appearance of senescent cells, which is associated with age-mediated loss of brain function (33), was prevented by XBP1s overexpression, whereas IRE1α deficiency accelerated the accumulation of senescent cells, suggesting that the UPR exerts global effects in sustaining the health of brain tissue during aging.…”

supporting

confidence: 92%

Control of mammalian brain aging by the unfolded protein response (UPR)

Cabral‐Miranda

Tamburini

Martínez

et al. 2020

Preprint

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Aging is the major risk factor for the development of dementia and neurodegenerative disorders, and the aging brain manifests severe deficits in buffering capacity by the proteostasis network. Accordingly, we investigated the significance of the unfolded protein response (UPR), a major signaling pathway that copes with endoplasmic reticulum (ER) stress, to normal mammalian brain aging. Genetic disruption of ER stress sensor IRE1α accelerated cognitive and motor dysfunction during aging. Exogenous bolstering of the UPR by overexpressing an active form of the transcription factor XBP1 restored synaptic and cognitive function in addition to reducing cell senescence.Remarkably, proteomic profiling of hippocampal tissue indicated that XBP1s expression corrected age-related alterations in synaptic function. Collectively, our data demonstrate that strategies to manipulate the UPR sustain healthy brain aging.One Sentence Summary: The IRE1/XBP1 pathway dictates when and how brain function declines during aging. Main Text:Normal aging is associated with progressive cognitive impairment, representing the most prevalent risk factor for the development of dementia in neurodegenerative disorders. Subtle structural and functional alterations in synapses are the main drivers of age-related cognitive decline (reviewed in 1), but the molecular mechanisms dictating these perturbations are still elusive. Decades of research have defined the hallmarks of

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supporting

confidence: 92%

Control of mammalian brain aging by the unfolded protein response (UPR)

Cabral‐Miranda

Tamburini

Martínez

et al. 2020

Preprint

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“…Because the proteostasis network (including chaperones, degradation factors, and trafficking factors) plays an essential role in controlling the biogenesis of membrane proteins, we evaluated how loss of LMAN1 affects the proteostasis network in the central nervous system [28,29]. It was previously reported that in Lman1−/− mouse liver, the total protein level of GRP78 increased substantially without significant induction of the unfolded protein response (UPR) genes, including Grp78, Grp94, Xbp1, Chop and Atf4 [27].…”

Section: Influence Of Lman1 Knockout On the Proteostasis Network In Tmentioning

confidence: 99%

LMAN1 (ERGIC-53) promotes trafficking of neuroreceptors

Zhang

2019

Biochemical and Biophysical Research Communications

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The endoplasmic reticulum-Golgi intermediate compartment aka LMAN1), which cycles between the endoplasmic reticulum (ER) and Golgi, is a known cargo receptor for a number of soluble proteins. However, whether LMAN1 plays a role as a trafficking factor in the central nervous system is largely unknown. Here, we determined the role of LMAN1 on endogenous protein levels of the Cys-loop superfamily of neuroreceptors, including gammaaminobutyric acid type A receptors (GABA A Rs), 5-hydroxytryptamine (serotonin) type 3 (5-HT 3 ) receptors, and nicotinic acetylcholine receptors (nAChRs). Knockdown of LMAN1 reduces the surface trafficking of endogenous β3 subunits of GABA A Rs in mouse hypothalamic GT1-7 neurons. Furthermore, Western blot analysis of brain homogenates from LMAN1 knockout mice demonstrated that loss of LMAN1 decreases the total protein levels of 5HT 3 A receptors and γ2 subunits of GABA A Rs. LMAN1 knockout regulates the ER proteostasis network by upregulating ERP44 without changing calnexin levels. Interestingly, despite the critical role of the glycanbinding function of LMAN1 in its other known cargo clients, LMAN1 interacts with GABA A Rs in a glycan-independent manner. In summary, LMAN1 is a trafficking factor for certain neuroreceptors in the central nervous system. This is the first report of LMAN1 function in membrane protein trafficking.

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“…The observations on cell-nonautonomous control of the HSR extend to the UPR ER and the UPR MT (Durieux et al 2011;Imanikia et al 2018;Martínez et al 2018;Zhang et al 2018). Perturbation of the mitochondrial electron transfer chain increases life span in both invertebrates and rodents through the activation of the UPR MT (Liu et al 2005;Copeland et al 2009;Durieux et al 2011).…”

Section: Cell-nonautonomous Regulation Of Organismal Proteostasismentioning

confidence: 99%

Cell-Nonautonomous Regulation of Proteostasis in Aging and Disease

Morimoto

2019

Cold Spring Harb Perspect Biol

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The functional health of the proteome is determined by properties of the proteostasis network (PN) that regulates protein synthesis, folding, macromolecular assembly, translocation, and degradation. In eukaryotes, the PN also integrates protein biogenesis across compartments within the cell and between tissues of metazoans for organismal health and longevity. Additionally, in metazoans, proteome stability and the functional health of proteins is optimized for development and yet declines throughout aging, accelerating the risk for misfolding, aggregation, and cellular dysfunction. Here, I describe the cell-nonautonomous regulation of organismal PN by tissue communication and cell stress-response pathways. These systems are robust from development through reproductive maturity and are genetically programmed to decline abruptly in early adulthood by repression of the heat shock response and other cell-protective stress responses, thus compromising the ability of cells and tissues to properly buffer against the cumulative stress of protein damage during aging. While the failure of multiple protein quality control processes during aging challenges cellular function and tissue health, genetic studies, and the identification of small-molecule proteostasis regulators suggests strategies that can be employed to reset the PN with potential benefit on cellular health and organismal longevity.

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ER Proteostasis Control of Neuronal Physiology and Synaptic Function

Cited by 91 publications

References 130 publications

Control of mammalian brain aging by the unfolded protein response (UPR)

Control of mammalian brain aging by the unfolded protein response (UPR)

LMAN1 (ERGIC-53) promotes trafficking of neuroreceptors

Cell-Nonautonomous Regulation of Proteostasis in Aging and Disease

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