ER stress inhibits neuronal death by promoting autophagy

Fouillet, Antoine; Levet, Clémence; Virgone, Angelique; Robin, Marion; Dourlen, Pierre; Rieusset, Jennifer; Belaidi, Élise; Ovize, Michel; Touret, Monique; Nataf, Serge; Mollereau, Bertrand

doi:10.4161/auto.19716

Cited by 186 publications

(152 citation statements)

References 57 publications

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“…In mammalian cells, ER stress preconditioning protects against brain ischemia and attenuates heart ischemia/reperfusion (22,23). More recent findings support the direct involvement of a hormesis mechanism in handling neuronal degeneration through preconditioning mediated by a dynamic balance between ER stress and autophagy (21). In C. elegans, the notion of hormesis has been previously related to the effect of oxidative stress on longevity and dauer diapause (31)(32)(33), and mildly elevated temperature on heat-induced necrosis (34).…”

Section: Hormesis Contributes To Er Stress Resistance In the Absence mentioning

confidence: 80%

“…ER hormesis has previously been described in Drosophila and mammalian cell systems (21)(22)(23). To test whether this mechanism is conserved in C. elegans, we first exposed wild-type animals to low doses of TM, which on their own have no effect on viability, followed by higher doses normally associated with decreased survival.…”

Section: Hpl-2 Plays Opposing Functions In the Intestine And Neuronalmentioning

confidence: 99%

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The Caenorhabditis elegans HP1 family protein HPL-2 maintains ER homeostasis through the UPR and hormesis

Kozlowski

Garvis

Bedet

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Cellular adaptation to environmental changes and stress relies on a wide range of regulatory mechanisms that are tightly controlled at several levels, including transcription. Chromatin structure and chromatin binding proteins are important factors contributing to the transcriptional response to stress. However, it remains largely unknown to what extent specific chromatin factors influence the response to distinct forms of stress in a developmental context. One of the best characterized stress response pathways is the unfolded protein response (UPR), which is activated by accumulation of misfolded proteins in the endoplasmic reticulum (ER). Here, we show that Caenorhabditis elegans heterochromatin protein like-2 (HPL-2), the homolog of heterochromatin protein 1 (HP1), downregulates the UPR in the intestine. Inactivation of HPL-2 results in an enhanced resistance to ER stress dependent on the X-box binding protein 1 (XBP-1)/inositol requiring enzyme 1 branch of the UPR and the closely related process of autophagy. Increased resistance to ER stress in animals lacking HPL-2 is associated with increased basal levels of XBP-1 activation and ER chaperone expression under physiological conditions, which may in turn activate an adaptive response known as ER hormesis. HPL-2 expression in intestinal cells is sufficient to rescue stress resistance, whereas expression in neuronal cells negatively influenced the ER stress response through a cell-nonautonomous mechanism. We further show that the retinoblastoma protein homolog LIN-35 and the LIN-13 zinc finger protein act in the same pathway as HPL-2 to limit the ER stress response. Altogether, our results point to multiple functions for HP1 in different cell types to maintain ER homeostasis.

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Section: Hormesis Contributes To Er Stress Resistance In the Absence mentioning

confidence: 80%

Section: Hpl-2 Plays Opposing Functions In the Intestine And Neuronalmentioning

confidence: 99%

The Caenorhabditis elegans HP1 family protein HPL-2 maintains ER homeostasis through the UPR and hormesis

Kozlowski

Garvis

Bedet

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…However, eIF2α phosphorylation is also an indicator of ER unfolded protein response (UPR ER ). Indeed, BiP/GRP78, the master regulator of UPR ER transduction pathway, [44][45][46] was upregulated in dYME1L del flies throughout their adulthood (Supplementary Figure S5a). In addition, the general cellular protein turnover mechanisms, autophagy and ubiquitin-proteasome system, were both activated in the mutant flies (Figures 6c and d).…”

Section: Resultsmentioning

confidence: 99%

Loss of Drosophila i-AAA protease, dYME1L, causes abnormal mitochondria and apoptotic degeneration

Liu

Daniels

et al. 2015

Cell Death Differ

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Mitochondrial AAA (ATPases Associated with diverse cellular Activities) proteases i-AAA (intermembrane space-AAA) and m-AAA (matrix-AAA) are closely related and have major roles in inner membrane protein homeostasis. Mutations of m-AAA proteases are associated with neuromuscular disorders in humans. However, the role of i-AAA in metazoans is poorly understood. We generated a deletion affecting Drosophila i-AAA, dYME1L (dYME1L del ). Mutant flies exhibited premature aging, progressive locomotor deficiency and neurodegeneration that resemble some key features of m-AAA diseases. dYME1L del flies displayed elevated mitochondrial unfolded protein stress and irregular cristae. Aged dYME1L del flies had reduced complex I (NADH/ubiquinone oxidoreductase) activity, increased level of reactive oxygen species (ROS), severely disorganized mitochondrial membranes and increased apoptosis. Furthermore, inhibiting apoptosis by targeting dOmi (Drosophila Htra2/Omi) or DIAP1, or reducing ROS accumulation suppressed retinal degeneration. Our results suggest that i-AAA is essential for removing unfolded proteins and maintaining mitochondrial membrane architecture. Loss of i-AAA leads to the accumulation of oxidative damage and progressive deterioration of membrane integrity, which might contribute to apoptosis upon the release of proapoptotic molecules such as dOmi. Containing ROS level could be a potential strategy to manage mitochondrial AAA protease deficiency.

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“…autophagy may also mediate the benefits of preconditioning in Drosophila and mouse Parkinson's disease models (Fouillet et al 2012;Matus et al 2012). In these studies, inhibition of autophagy was found to impair endoplasmic reticulum stress-induced protection.…”

Section: Adaptation and Sensitization To Proteotoxic Stressmentioning

confidence: 99%

Adaptation and Sensitization to Proteotoxic Stress

Leak

2013

Dose-Response

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ᮀ Although severe stress can elicit toxicity, mild stress often elicits adaptations. Here we review the literature on stress-induced adaptations versus stress sensitization in models of neurodegenerative diseases. We also describe our recent findings that chronic proteotoxic stress can elicit adaptations if the dose is low but that high-dose proteotoxic stress sensitizes cells to subsequent challenges. In these experiments, long-term, low-dose proteasome inhibition elicited protection in a superoxide dismutase-dependent manner. In contrast, acute, high-dose proteotoxic stress sensitized cells to subsequent proteotoxic challenges by eliciting catastrophic loss of glutathione. However, even in the latter model of synergistic toxicity, several defensive proteins were upregulated by severe proteotoxicity. This led us to wonder whether high-dose proteotoxic stress can elicit protection against subsequent challenges in astrocytes, a cell type well known for their resilience. In support of this new hypothesis, we found that the astrocytes that survived severe proteotoxicity became harder to kill. The adaptive mechanism was glutathione dependent. If these findings can be generalized to the human brain, similar endogenous adaptations may help explain why neurodegenerative diseases are so delayed in appearance and so slow to progress. In contrast, sensitization to severe stress may explain why defenses eventually collapse in vulnerable neurons.

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ER stress inhibits neuronal death by promoting autophagy

Cited by 186 publications

References 57 publications

The Caenorhabditis elegans HP1 family protein HPL-2 maintains ER homeostasis through the UPR and hormesis

The Caenorhabditis elegans HP1 family protein HPL-2 maintains ER homeostasis through the UPR and hormesis

Loss of Drosophila i-AAA protease, dYME1L, causes abnormal mitochondria and apoptotic degeneration

Adaptation and Sensitization to Proteotoxic Stress

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