Adaptation and Sensitization to Proteotoxic Stress

Leak, Rehana K.

doi:10.2203/dose-response.13-016.leak

Cited by 13 publications

(12 citation statements)

References 246 publications

(262 reference statements)

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“…Unlike what we observed in astrocytes, severe stress has been observed to weaken surviving neurons in previous studies, consistent with the dual hit hypothesis of neurodegeneration, whereby dual hits synergize in their toxic effects on neurons [68, 88–95]. In other words, the effect of stress is likely to be both injury and cell-type dependent and may also vary with age, among other variables [96]. Thus, in all likelihood, cell fate is determined by genetic determinants of susceptibility as well as a convergence of all previous stressors.…”

Section: Discussionsupporting

confidence: 90%

“…Our studies therefore extend the neuroprotective capacities of injured astrocytes and provide concrete evidence that stress does not need to be low in concentration to elicit adaptive defenses. Indeed, most authors would argue that severe or high-dose stress only weakens cells, consistent with the two-hit hypothesis of neurodegeneration [88, 90, 96, 161–164]. Furthermore, many authors have suggested that stressed astrocytes exacerbate injury in neighboring neurons [14–19] and that astrocytes have a strong potential for dysfunction despite their normal roles in cellular defense and homeostasis [165].…”

Section: Discussionmentioning

confidence: 82%

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Astrocytes Surviving Severe Stress Can Still Protect Neighboring Neurons from Proteotoxic Injury

et al. 2015

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Astrocytes are one of the major cell types to combat cellular stress and protect neighboring neurons from injury. In order to fulfill this important role, astrocytes must sense and respond to toxic stimuli, perhaps including stimuli that are severely stressful and kill some of the astrocytes. The present study demonstrates that primary astrocytes that managed to survive severe proteotoxic stress were protected against subsequent challenges. These findings suggest that the phenomenon of preconditioning or tolerance can be extended from mild to severe stress for this cell type. Astrocytic stress adaptation lasted at least 96 hours, the longest interval tested. Heat shock protein 70 (Hsp70) was raised in stressed astrocytes, but inhibition of neither Hsp70 nor Hsp32 activity abolished their resistance against a second proteotoxic challenge. Only inhibition of glutathione synthesis abolished astrocytic stress adaptation, consistent with our previous report. Primary neurons were plated upon previously stressed astrocytes and the co-cultures were then exposed to another proteotoxic challenge. Severely stressed astrocytes were still able to protect neighboring neurons against this injury and the protection was unexpectedly independent of glutathione synthesis. Stressed astrocytes were even able to protect neurons after simultaneous application of proteasome and Hsp70 inhibitors, which otherwise elicited synergistic, severe loss of neurons when applied together. Astrocyte-induced neuroprotection against proteotoxicity was not elicited with astrocyte-conditioned media, suggesting that physical cell-to-cell contacts may be essential. These findings suggest that astrocytes may adapt to severe stress so that they can continue to protect neighboring cell types from profound injury.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 82%

Astrocytes Surviving Severe Stress Can Still Protect Neighboring Neurons from Proteotoxic Injury

et al. 2015

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“…In the present study, we developed a unique model of severe hippocampal stress in which to test new therapies. Our studies are based on the assumption that stress vulnerability and stress tolerance can be quantified by exposing previously stressed cells to a second stressful challenge and subsequently measuring viability (Leak, ). If the dual hits are synergistic in their toxic effects, the first exposure is hypothesized to sensitize cells to the second hit.…”

Section: Introductionmentioning

confidence: 99%

“…If the dual hits are synergistic in their toxic effects, the first exposure is hypothesized to sensitize cells to the second hit. This phenomenon of stress exacerbation is known as the dual or two‐hit hypothesis of neurodegeneration (Carvey et al, ; Leak, ). Many authors have applied the dual ‐ hit hypothesis to the hippocampus, in terms of epilectic seizure activity, schizophrenia, temporal sclerosis, memory loss, and Alzheimer's disease (McCarley et al, ; Hoffmann et al, ; Lewis, ; Somera‐Molina et al, ; Zhu et al, ; Ouardouz et al, ; Llorente et al, ; Dalton et al, ; Hill et al, ; Hamelin and Depaulis, ).…”

Section: Introductionmentioning

confidence: 99%

Synergistic stress exacerbation in hippocampal neurons: Evidence favoring the dual‐hit hypothesis of neurodegeneration

et al. 2016

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The dual hit hypothesis of neurodegeneration states that severe stress sensitizes vulnerable cells to subsequent challenges so that the two hits are synergistic in their toxic effects. Although the hippocampus is vulnerable to a number of neurodegenerative disorders, there are no models of synergistic cell death in hippocampal neurons in response to combined proteotoxic and oxidative stressors, the two major characteristics of these diseases. Therefore, we developed a relatively high-throughput dual hit model of stress synergy in primary hippocampal neurons. In order to increase the rigor of our study and strengthen our interpretations, we employed three independent, unbiased viability assays at multiple timepoints. Stress synergy was elicited when hippocampal neurons were treated with the proteasome inhibitor MG132 followed by exposure to the oxidative toxicant paraquat, but only after 48h. MG132 and paraquat only elicited additive effects 24h after the final hit and even loss of heat shock protein 70 activity and glutathione did not promote stress synergy at this early timepoint. Dual hits of MG132 elicited modest glutathione loss and slightly synergistic toxic effects 48h after the second hit, but only at some concentrations and only according to two viability assays (metabolic fitness and cytoskeletal integrity). The thiol N-acetyl cysteine protected hippocampal neurons against dual MG132/MG132 hits but not dual MG132/paraquat hits. Our findings support the view that proteotoxic and oxidative stress propel and propagate each other in hippocampal neurons, leading to synergistically toxic effects, but not as the default response and only after a delay. The neuronal stress synergy observed here lies in contrast to astrocytic responses to dual hits, because astrocytes that survive severe proteotoxic stress resist additional cell loss following second hits. In conclusion, we present a new model of hippocampal vulnerability in which to test therapies, because neuroprotective treatments that are effective against severe, synergistic stress are more likely to succeed in the clinic.

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“…In some systems, the cells that survive severe stress are not resistant, but are actually sensitized to subsequent stress, so that the two hits of severe stress are synergistic in their toxic effects in these populations (Boger et al 2010;Carvey et al 2006;Gao and Hong 2011;Manning-Bog and Langston 2007;Sulzer 2007;Unnithan et al 2012Unnithan et al , 2013Weidong et al 2009;Zhu et al 2001Zhu et al , 2007. In short, one might expect the direction of the stress response, i.e., whether it will elicit pro-survival or pro-death responses, to depend on cell type, heat shock protein expression, antioxidant defenses, dose and duration of the injury, previous exposures to other stressors, brain region, animal age, nutrient intake, physical activity levels, disease stage, and numerous other endogenous and environmental variables (Leak 2014).…”

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confidence: 99%

Heat shock proteins in neurodegenerative disorders and aging

Leak

2014

J. Cell Commun. Signal.

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144

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Many members of the heat shock protein family act in unison to refold or degrade misfolded proteins. Some heat shock proteins also directly interfere with apoptosis. These homeostatic functions are especially important in proteinopathic neurodegenerative diseases, in which specific proteins misfold, aggregate, and kill cells through proteotoxic stress. Heat shock protein levels may be increased or decreased in these disorders, with the direction of the response depending on the individual heat shock protein, the disease, cell type, and brain region. Aging is also associated with an accrual of proteotoxic stress and modulates expression of several heat shock proteins. We speculate that the increase in some heat shock proteins in neurodegenerative conditions may be partly responsible for the slow progression of these disorders, whereas the increase in some heat shock proteins with aging may help delay senescence. The protective nature of many heat shock proteins in experimental models of neurodegeneration supports these hypotheses. Furthermore, some heat shock proteins appear to be expressed at higher levels in longer-lived species. However, increases in heat shock proteins may be insufficient to override overwhelming proteotoxic stress or reverse the course of these conditions, because the expression of several other heat shock proteins and endogenous defense systems is lowered. In this review we describe a number of stressinduced changes in heat shock proteins as a function of age and neurodegenerative pathology, with an emphasis on the heat shock protein 70 (Hsp70) family and the two most common proteinopathic disorders of the brain, Alzheimer's and Parkinson's disease.

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Adaptation and Sensitization to Proteotoxic Stress

Cited by 13 publications

References 246 publications

Astrocytes Surviving Severe Stress Can Still Protect Neighboring Neurons from Proteotoxic Injury

Astrocytes Surviving Severe Stress Can Still Protect Neighboring Neurons from Proteotoxic Injury

Synergistic stress exacerbation in hippocampal neurons: Evidence favoring the dual‐hit hypothesis of neurodegeneration

Heat shock proteins in neurodegenerative disorders and aging

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