Nilotinib-induced autophagic changes increase endogenous parkin level and ubiquitination, leading to amyloid clearance.
Nilotinib-induced autophagic changes increase endogenous parkin level and ubiquitination, leading to amyloid clearance.
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DOI：
10.1007/s00109-013-1112-3
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发表时间：
2014-04
影响因子：
4.7
通讯作者：
Moussa, Charbel E-H
中科院分区：
文献类型：
--
作者：
Lonskaya, Irina;Hebron, Michaeline L.;Desforges, Nicole M.;Schachter, Joel B.;Moussa, Charbel E-H
Alzheimer’s disease (AD) is a neurodegenerative disorder associated with amyloid accumulation and autophagic changes. Parkin is an E3 ubiquitin ligase involved in proteasomal and autophagic clearance. We previously demonstrated decreased parkin solubility and interaction with the key autophagy enzyme Beclin-1 in AD, but tyrosine kinase inhibition restored parkin-Beclin-1 interaction. In the current studies we determined the mechanisms of Nilotinib-induced parkin-Beclin-1 interaction, which leads to amyloid clearance. Nilotinib increased endogenous parkin levels and ubiquitination, which may enhance parkin recycling via the proteasome, leading to increased activity and interaction with Beclin-1. Parkin solubility was decreased and autophagy was altered in amyloid expressing mice, suggesting that amyloid stress affects parkin stability, leading to failure of protein clearance via the lysosome. Isolation of autophagic vacuoles revealed amyloid and parkin accumulation in autophagic compartments but Nilotinib decreased insoluble parkin levels and facilitated amyloid deposition into lysosomes in wild type, but not parkin−/− mice, further underscoring an essential role for endogenous parkin in amyloid clearance. These results suggest that Nilotinib boosts the autophagic machinery, leading to increased level of endogenous parkin that undergoes ubiquitination and interacts with Beclin-1 to facilitate amyloid clearance. These data suggest that Nilotinib-mediated autophagic changes may trigger parkin response via increased protein levels, providing a therapeutic strategy to reduce Aβ and Tau in AD.
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作者：
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DOI：
10.1083/jcb.201210111
发表时间：
2013-01-21
期刊：
The Journal of cell biology
影响因子：
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作者：
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通讯作者：
Youle RJ