Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease

Ravikumar, Brinda; Vacher, Coralie; Berger, Zdenek; Davies, J. Eric; Luo, Shouqing; Oroz, Lourdes Garcia; Salvatore, Francesco; Easton, Douglas F.; Duden, Rainer; O’Kane, Cahir J.; Rubinsztein, David C.

doi:10.1038/ng1362

Cited by 2,179 publications

(1,891 citation statements)

References 48 publications

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“…mTOR inhibitors induce apoptosis in some types of tumor cells (Hosoi et al, 1999;Nepomuceno et al, 2003;Majumder et al, 2004;Avellino et al, 2005), whereas they trigger autophagy in other settings (Noda and Ohsumi, 1998;Gutierrez et al, 2004;Kanazawa et al, 2004;Ravikumar et al, 2004) as well as in malignant glioma cells as shown in this study and our previous investigation (Takeuchi et al, 2005). Autophagy is a process by which cells degrade and recycle proteins and intracellular components in response to stress or starvation (Klionsky and Emr, 2000;Levine and Klionsky, 2004;Shintani and Klionsky, 2004).…”

Section: Discussionsupporting

confidence: 64%

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Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells

et al. 2006

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The mammalian target of rapamycin (mTOR) plays a central role in regulating the proliferation of malignant glioma cells, and mTOR-specific inhibitors such as rapamycin analogs are considered as promising therapy for malignant gliomas. However, the efficacy of mTOR inhibitors alone in the treatment of patients with malignant gliomas is only modest, potentially because these agents rather than acting as mTOR kinase inhibitors instead interfere with the function of only mTOR/raptor (regulatory-associated protein of mTOR) complex and thus do not perturb all mTOR functions. The purpose of this study was to determine whether global inhibition of the mTOR molecule enhances the antitumor effect of rapamycin on malignant glioma cells. We showed that rapamycin induced autophagy and that inhibition of autophagy by small interfering RNA (siRNA) directed against autophagyrelated gene Beclin 1 attenuated the cytotoxicity of rapamycin in rapamycin-sensitive tumor cells, indicating that the autophagy was a primary mediator of rapamycin's antitumor effect rather than a protective response. Exogenous expression of an mTOR mutant interfering with its kinase activity markedly enhanced the incidence of rapamycin-induced autophagy. Moreover, silencing of mTOR with siRNA augmented the inhibitory effect of rapamycin on tumor cell viability by stimulating autophagy. Importantly, not only rapamycin-sensitive malignant glioma cells with PTEN mutations but also rapamycin-resistant malignant glioma cells with wild-type PTEN were sensitized to rapamycin by mTOR siRNA. These results indicate that rapamycin-induced autophagy is one of the agent's antitumor effects and that silencing or inhibiting mTOR kinase activity could enhance the effectiveness of rapamycin.

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Section: Discussionsupporting

confidence: 64%

“…Induction of autophagy in malignant glioma cells by rapamycin Autophagy is detected in a variety of cells treated with rapamycin (Noda and Ohsumi, 1998;Gutierrez et al, 2004;Kanazawa et al, 2004;Ravikumar et al, 2004). We used electron microscopic analysis to determine whether rapamycin induces autophagy in our malignant glioma cells.…”

Section: Resultsmentioning

confidence: 99%

Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells

et al. 2006

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“…30,31 Pharmacological induction of autophagy promoted clearance of protein aggregates and delayed neurodegeneration as well as behavioral symptoms in animal models of neurodegenerative diseases. 14,32,33 We have recently shown that genetic and pharmacological ablation of autophagy promoted exocytosis and transcellular transmission of a-synuclein aggregates. 34 Consistent with the role of autophagy in aggregate clearance, our data showed that impairment in autophagic flux upon PLD1 inhibition resulted in accumulation of a-synuclein in APs.…”

Section: Discussionmentioning

confidence: 99%

Phospholipase D1 regulates autophagic flux and clearance of α-synuclein aggregates

et al. 2014

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Many neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are characterized by abnormal accumulations of aggregated proteins. Brains in these diseases also show accumulation of autophagic vesicles in the neuronal cytoplasm, suggesting impairment of the autophagic process. As autophagy involves de novo membrane production and vesicle fusion, extensive changes in lipid molecules are necessary. However, the involvement of signaling lipid-modifying enzymes in autophagy and their roles in neurodegenerative diseases are not clear. Using specific inhibitor, we show that loss of phospholipase D1 (PLD1) activity resulted in an accumulation of microtubule-associated protein light chain 3 (LC3), p62, and polyubiquitinated proteins, signs representing malfunction in autophagic flux. Fluorescence and electron microscopic analyses demonstrated impaired fusion of autophagosomes with lysosomes, resulting in accumulation of autophagosomes. Within the cells with impaired autophagic flux, a-synuclein aggregates accumulated in autophagosomes. Knockdown of PLD1 expression using small interfering RNA also resulted in impaired autophagic flux and accumulation of a-synuclein aggregates in autophagosomes. Neuronal toxicity caused by a-synuclein accumulation was rescued by overexpression of PLD1; however, expression of activity-deficient mutant, PLD1-KRM, showed reduced rescue effects. Finally, we demonstrated that both PLD activity and expression levels were reduced in brain tissues of dementia with Lewy bodies (DLB) patients, whereas the amounts of a-synuclein and p62 were increased in the same tissue samples. Collectively, these results suggest that insufficient PLD activity, and therefore, the changes in phospholipid compositions within membranes, might be an important contributor to impaired autophagic process and protein accumulation in Lewy body diseases.

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“…16,17 Inhibition of autophagy induces aggregate formation, whereas rapamycin-induced upregulation of autophagy reduces it. [18][19][20][21] Furthermore, amelioration of neurodegeneration and improvement of behavior were reported in a D. melanogaster Huntington model following treatment with a rapamycin analog, CCI-779. 21 It has been speculated that aggregates can be degraded by autophagy Figure 2 Molecular mechanism of autophagy regulation and autophagosome formation.…”

Section: Intracellular Clearance By 'Baseline Autophagy': Antidegenermentioning

confidence: 97%

“…[18][19][20][21] Furthermore, amelioration of neurodegeneration and improvement of behavior were reported in a D. melanogaster Huntington model following treatment with a rapamycin analog, CCI-779. 21 It has been speculated that aggregates can be degraded by autophagy Figure 2 Molecular mechanism of autophagy regulation and autophagosome formation. Insulin is thought to be one of the major suppressive factors for autophagy.…”

Section: Intracellular Clearance By 'Baseline Autophagy': Antidegenermentioning

confidence: 97%

The pleiotropic role of autophagy: from protein metabolism to bactericide

2005

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Autophagy is in principle a nonselective, bulk degradation system within cells, with a contribution to intracellular protein degradation estimated to be as large as that of the ubiquitin--proteasome system. The primary roles of autophagy are baseline turnover of intracellular proteins and organelles, production of amino acids in nutrient emergency, and regression of retired tissues. These functions guarantee rejuvenation and adaptation to adverse conditions, and even underlie dynamic processes such as development/metamorphosis. In addition, several other roles for autophagy have recently been discovered, such as presentation of endogenous antigens and degradation of invasive bacteria. This review will discuss the biological significance of autophagy from yeast to higher eukaryotes.

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Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease

Cited by 2,179 publications

References 48 publications

Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells

Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells

Phospholipase D1 regulates autophagic flux and clearance of α-synuclein aggregates

The pleiotropic role of autophagy: from protein metabolism to bactericide

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