Stress, Aging, and Neurodegenerative Disease

Morimoto, Richard I.

doi:10.1056/nejmcibr065573

Cited by 83 publications

(74 citation statements)

References 4 publications

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“…[1][2][3][4][5][6][7][8][9][10]23,[33][34][35][36][37][43][44][45] The prevention of amyloidogenesis by a kinetic stabilizer approach has recently been demonstrated to halt the progression of nervous system degeneration in familial amyloid polyneuropathy associated with the amyloidogenesis of transthyretin. Thus, it is logical that the removal of protein aggregates would be crucial for protein homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…Identifying the molecular machinery responsible for the mammalian disaggregase activity and, ultimately, adapting this machinery offer the prospect of ameliorating age-related degenerative diseases in which cytotoxicity is genetically linked to the process of amyloidogenesis. 5,[10][11][12][13][14][15][16][17][18][19]22,30,[33][34][35][36][37] Results…”

Section: Introductionmentioning

confidence: 99%

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Discovery and characterization of a mammalian amyloid disaggregation activity

Murray¹,

Solomon²,

Wang³

et al. 2010

Protein Science

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The formation of amyloid, a cross-b-sheet fibrillar aggregate, is associated with a variety of aging-associated degenerative diseases. Herein, we report the existence of a mammalian amyloid disaggregase activity that is present in all tissues and cell types tested. Homogenates from mammalian tissues and cell lines are able to disaggregate amyloid fibrils composed of amyloid b (Ab) 1-40 or the 8 kDa plasma gelsolin fragment. The mammalian disaggregase activity is sensitive to proteinase K digestion and can be uncoupled from proteolysis activity using a protease inhibitor cocktail. Amyloid disaggregation and proteolysis activities are remarkably resistant to changes in temperature and pH. Identification and manipulation of the proteins responsible for the amyloid disaggregation/degradation activities offers the possibility of ameliorating aggregation-associated diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovery and characterization of a mammalian amyloid disaggregation activity

Murray¹,

Solomon²,

Wang³

et al. 2010

Protein Science

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“…In fact, assays conducted on the nematode C. elegans have shown the existence of genes whose expression results in nuclear receptors and proteins of the insulin/IGF-1 signaling (IIS) pathway that are involved in environmental stress response and life span. Certainly, a decrease in the activity of the IIS pathway modifies development, raises stress resistance, protects against proteotoxicity, and extends life span in worms, flies, and mice (Morimoto 2006). The IIS pathway comprises a receptor that signals to a PI3 kinase/AKT conserved pathway which, finally, downregulates to DAF-16 activity by inhibiting its translocation into the nucleus.…”

Section: Introductionmentioning

confidence: 99%

“…Several studies on oxidative stress have been carried out in animal models, including the nematode Caenorhabditis elegans (Kahn et al 2008;Koon and Kubiseski 2010;Morimoto 2006), the fruit fly Drosophila Melanogaster (Ahamed et al 2010;Bahadorani et al 2010), and mice (Straadt et al 2010). C. elegans in particular exhibits defense mechanisms against oxidative stress similar to those in human beings, such as antioxidant enzymes, glutathione system, and stress response signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, after a stressful stimulus in C. elegans, cellular response is based on induction of stress proteins or heat shock proteins, through inhibition of the IIS pathway (Morimoto 2006). Genetic manipulations to overexpress individual chaperones, like Hsp90 and Hsp70, resulted in a subtle extension of life span (Morley and Morimoto 2004); however, the small chaperone Hsp16 seemed to be more efficient in worms (Soti and Csermely 2007), particularly HSP-16.2 that is often used as an indicator of increases in thermal and oxidative stress (Hartwig et al 2009;Rea et al 2005;Strayer et al 2003;Wiegant et al 2009;Wu et al 2006;Xiao et al 2009).…”

Section: Introductionmentioning

confidence: 99%

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Inactivation of GABAA receptor is related to heat shock stress response in organism model Caenorhabditis elegans

Camargo

Elizalde

Trujillo

et al. 2016

Cell Stress and Chaperones

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The mechanisms underlying oxidative stress (OS) resistance are not completely clear. Caenorhabditis elegans (C. elegans) is a good organism model to study OS because it displays stress responses similar to those in mammals. Among these mechanisms, the insulin/IGF-1 signaling (IIS) pathway is thought to affect GABAergic neurotransmission. The aim of this study was to determine the influence of heat shock stress (HS) on GABAergic activity in C. elegans. For this purpose, we tested the effect of exposure to picrotoxin (PTX), gammaaminobutyric acid (GABA), hydrogen peroxide, and HS on the occurrence of a shrinking response (SR) after nose touch stimulus in N2 (WT) worms. Moreover, the effect of HS on the expression of UNC-49 (GABA A receptor ortholog) in the EG1653 strain and the effect of GABA and PTX exposure on HSP-16.2 expression in the TJ375 strain were analyzed. PTX 1 mM-or H 2 O 2 0.7 mM-exposed worms displayed a SR in about 80 % of trials. GABA exposure did not cause a SR. HS prompted the occurrence of a SR as did PTX 1 mM or H 2 O 2 0.7 mM exposure. In addition, HS increased UNC-49 expression, and PTX augmented HSP-16.2 expression. Thus, the results of the present study suggest that oxidative stress, through either H 2 O 2 exposure or application of heat shock, inactivates the GABAergic system, which subsequently would affect the oxidative stress response, perhaps by enhancing the activity of transcription factors DAF-16 and HSF-1, both regulated by the IIS pathway and related to hsp-16.2 expression.

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