Inhibition of endoplasmic reticulum stress counteracts neuronal cell death and protein aggregation caused by N-terminal mutant huntingtin proteins

Reijonen, Sami; Putkonen, Noora; Nørremølle, Anne; Lindholm, Dan; Korhonen, Laura

doi:10.1016/j.yexcr.2007.12.025

Cited by 139 publications

(118 citation statements)

References 38 publications

(94 reference statements)

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“…It had been reported before that expression of pathogenic Htt causes ER stress 7,11,12 , but the molecular form of Htt that causes this effect had not been determined. On the other hand, there is increasing evidence that Htt oligomers and not aggregates are the cytotoxic agent 3,15,16 , although it is not clear what cellular pathways they affect.…”

Section: Resultsmentioning

confidence: 99%

“…Interference with the UPS inhibits cytosolic protein degradation as well as endoplasmic reticulum (ER)-associated protein degradation (ERAD) 7,8 , a pathway that reduces the protein load in the ER 9,10 . Inhibition of ERAD leads to the accumulation of unfolded or misfolded proteins in the ER, ER stress and the activation of the unfolded protein response (UPR) 7,11,12 , (reviewed in refs 13,14). There is increasing evidence that Htt oligomers and not aggregates are the cytotoxic agent in HD 3,15,16 , although the subject still remains controversial.…”

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confidence: 99%

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Soluble forms of polyQ-expanded huntingtin rather than large aggregates cause endoplasmic reticulum stress

2013

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In Huntington's disease, as in other neurodegenerative diseases, it was initially thought that insoluble protein aggregates are the toxic species. However, growing evidence implicates soluble oligomeric polyglutamine-expanded huntingtin in cytotoxicity. Here we show that pathogenic huntingtin inhibits endoplasmic reticulum (ER)-associated degradation and induces ER stress before its aggregation into visible inclusions. All three branches of the unfolded protein response are activated. ER stress can be compensated by overexpression of p97/VCP, suggesting its sequestration by pathogenic huntingtin as a main cause. Stress correlates with the presence of huntingtin oligomers and is independent of continual huntingtin synthesis. Stress levels, measured in striatal neurons, are stabilized but only slowly subside on huntingtin aggregation into inclusions. Our results can be explained by the constant conversion of huntingtin monomers to toxic oligomers; large aggregates sequester the former, precluding further conversion, whereas pre-existing toxic oligomers are only gradually depleted.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Soluble forms of polyQ-expanded huntingtin rather than large aggregates cause endoplasmic reticulum stress

2013

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“…Indeed, protein aggregates and markers of the ER stress response have been observed in dying neurons in animal models of cerebral ischemia Kumar et al, 2001) and Alzheimer's, Parkinson's, and Huntingtin's diseases (Ryu et al, 2002;Katayama et al, 2004;Reijonen et al, 2008). Therefore, it has become essential to identify the signaling pathways that regulate ER-stress-induced neuronal death.…”

Section: Discussionmentioning

confidence: 99%

Neuronal Apoptosis Induced by Endoplasmic Reticulum Stress Is Regulated by ATF4–CHOP-Mediated Induction of the Bcl-2 Homology 3-Only Member PUMA

Galehdar¹,

Swan²,

Fuerth³

et al. 2010

J. Neurosci.

288

228

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An increasing body of evidence points to a key role of endoplasmic reticulum (ER) stress in acute and chronic neurodegenerative conditions. Extensive ER stress can trigger neuronal apoptosis, but the signaling pathways that regulate this cell death remain unclear. In the present study, we demonstrate that PUMA, a Bcl-2 homology 3 (BH3)-only member of the Bcl-2 family, is transcriptionally activated in cortical neurons by ER stress and is essential for ER-stress-induced cell death. PUMA is known to be a key transcriptional target of p53, but we have found that ER stress triggers PUMA induction and cell death through a p53-independent mechanism mediated by the ER-stress-inducible transcription factor ATF4 (activating transcription factor 4). Specifically, we demonstrate that ectopic expression of ATF4 sensitizes mouse cortical neurons to ER-stress-induced apoptosis and that ATF4-deficient neurons exhibit markedly reduced levels of PUMA expression and cell death. However, chromatin immunoprecipitation experiments suggest that ATF4 does not directly regulate the PUMA promoter. Rather, we found that ATF4 induces expression of the transcription factor CHOP (C/EBP homologous protein) and that CHOP in turn activates PUMA induction. Specifically, we demonstrate that CHOP binds to the PUMA promoter during ER stress and that CHOP knockdown attenuates PUMA induction and neuronal apoptosis. In summary, we have identified a key signaling pathway in ER-stress-induced neuronal death involving ATF4 -CHOP-mediated transactivation of the proapoptotic Bcl-2 family member PUMA. We propose that this pathway may be an important therapeutic target relevant to a number of neurodegenerative conditions.

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“…[48][49][50][51][52][53] Furthermore, other UPR modulators (such as salubrinal, several chemical chaperones, overexpression of GRP78 and downregulation of SCAMP5, Rrs1 and ASK1) have been successfully used in alleviating HD-associated phenotypes. 10,49,52,[54][55][56][57][58][59][60] Recently, guanabenz, an α-2 adrenergic receptor agonist, was reported to exhibit significant protection against apoptosis via selective modulation of the UPR. 11 Unlike guanabenz, which antagonizes ER stressinduced apoptosis by blocking most UPR pathways, glucocorticoids exert their protective effects downstream of and/or independent of the major arms of the UPR (Figures 1 and 2).…”

Section: Discussionmentioning

confidence: 99%

The transrepression arm of glucocorticoid receptor signaling is protective in mutant huntingtin-mediated neurodegeneration

et al. 2015

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The unfolded protein response (UPR) occurs following the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and orchestrates an intricate balance between its prosurvival and apoptotic arms to restore cellular homeostasis and integrity. However, in certain neurodegenerative diseases, the apoptotic arm of the UPR is enhanced, resulting in excessive neuronal cell death and disease progression, both of which can be overcome by modulating the UPR. Here, we describe a novel crosstalk between glucocorticoid receptor signaling and the apoptotic arm of the UPR, thus highlighting the potential of glucocorticoid therapy in treating neurodegenerative diseases. Several glucocorticoids, but not mineralocorticoids, selectively antagonize ER stress-induced apoptosis in a manner that is downstream of and/or independent of the conventional UPR pathways. Using GRT10, a novel selective pharmacological modulator of glucocorticoid signaling, we describe the importance of the transrepression arm of the glucocorticoid signaling pathway in protection against ER stress-induced apoptosis. Furthermore, we also observe the protective effects of glucocorticoids in vivo in a Drosophila model of Huntington's disease (HD), wherein treatment with different glucocorticoids diminished rhabdomere loss and conferred neuroprotection. Finally, we find that growth differentiation factor 15 has an important role downstream of glucocorticoid signaling in antagonizing ER stress-induced apoptosis in cells, as well as in preventing HD-mediated neurodegeneration in flies. Thus, our studies demonstrate that this novel crosstalk has the potential to be effectively exploited in alleviating several neurodegenerative disorders.

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Inhibition of endoplasmic reticulum stress counteracts neuronal cell death and protein aggregation caused by N-terminal mutant huntingtin proteins

Cited by 139 publications

References 38 publications

Soluble forms of polyQ-expanded huntingtin rather than large aggregates cause endoplasmic reticulum stress

Soluble forms of polyQ-expanded huntingtin rather than large aggregates cause endoplasmic reticulum stress

Neuronal Apoptosis Induced by Endoplasmic Reticulum Stress Is Regulated by ATF4–CHOP-Mediated Induction of the Bcl-2 Homology 3-Only Member PUMA

The transrepression arm of glucocorticoid receptor signaling is protective in mutant huntingtin-mediated neurodegeneration

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