2010
DOI: 10.1126/science.1190354
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An Autophagy-Enhancing Drug Promotes Degradation of Mutant α 1 -Antitrypsin Z and Reduces Hepatic Fibrosis

Abstract: In the classical form of alpha1-antitrypsin (AT) deficiency, a point mutation in AT alters the folding of a liver-derived secretory glycoprotein and renders it aggregation-prone. In addition to decreased serum concentrations of AT, the disorder is characterized by accumulation of the mutant alpha1-antitrypsin Z (ATZ) variant inside cells, causing hepatic fibrosis and/or carcinogenesis by a gain-of-toxic function mechanism. The proteasomal and autophagic pathways are known to mediate degradation of ATZ. Here we… Show more

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Cited by 563 publications
(538 citation statements)
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“…It also facilitates the clearance of soluble EGFP-HDQ74 and mutant synucleins [47] . Furthermore, the mood stabilizing drugs carbamazepine [50] and valproic acid [51] , which lower intracellular inositol levels, were also found to activate autophagy. These findings suggest that IMPase inhibitors may be a valuable strategy for the treatment of neurodegenerative diseases by upregulating autophagy.…”
Section: Small Molecule Enhancers Of Rapamycinmentioning
confidence: 99%
“…It also facilitates the clearance of soluble EGFP-HDQ74 and mutant synucleins [47] . Furthermore, the mood stabilizing drugs carbamazepine [50] and valproic acid [51] , which lower intracellular inositol levels, were also found to activate autophagy. These findings suggest that IMPase inhibitors may be a valuable strategy for the treatment of neurodegenerative diseases by upregulating autophagy.…”
Section: Small Molecule Enhancers Of Rapamycinmentioning
confidence: 99%
“…Many drugs and compounds that modulate autophagy are currently receiving considerable attention [11,89,108]. These include, for example, autophagy inducers such as the mTORC1 inhibitor rapamycin [109] and its analogues (e.g., CCI-779 [109], RAD001 [110,111], and AP23573 [112]), mTOR kinase inhibitors (e.g., Torin 1 [113], and PP242 [114]), trehalose [115,116], carbamazepine [117], and the newly identified autophagy-inducing peptide Tatbeclin 1 [118]; autophagy inhibitors such as chloroquine [119,120] and hydroxychloroquine [121], Lys05 [122], 3-methyladenine [123] and its derivatives [124], PIK3C3 inhibitors [125], ATG4B inhibitors [126,127], and ATG7 inhibitors [128,129]. Autophagy-modulating drugs that are currently used in clinical trials are summarized in Table 2.…”
Section: Conclusion and Future Prospectsmentioning
confidence: 99%
“…28 The removal of harmful cellular aggregates by inducing autophagy has been tested in experimental models of a1 antitrypsin deficiency. 29 …”
Section: Tissue Homeostasis and Renovationmentioning
confidence: 99%
“…Carbamazepine has been shown to reduce these inclusions in mouse models by induction of autophagy along with reduced liver injury and fibrosis. 29 Carbamazepine induces autophagy through a mTOR independent pathway as Rapamaycin has no effect on mutant AT protein aggregate degradation. There are other mTOR independent autophagy inducers including lithium, sodium valproate, verapamil, loperamide, amiodarone, nimodipine and nitrendipine but their role in AT-deficiency induced liver injury needs to be defined.…”
Section: Targeting Autophagy In Alfa-1 Antitrypsin Deficiencymentioning
confidence: 99%