Nilotinib-induced autophagic changes increase endogenous parkin level and ubiquitination, leading to amyloid clearance
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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.
Parkin solubility (stability) is decreased in AD and APP transgenic mice.
Nilotinib-induced autophagic changes increase endogenous parkin level.
Increased parkin level leads to ubiquitination and proteasomal recycling.
Re-cycling decreases insoluble parkin and increases parkin–beclin-1 interaction.
Beclin-1–parkin interaction enhances amyloid clearance.
KeywordsUbiquitination Parkin Autophagy Tau Amyloid Alzheimer's
These studies were supported by NIH grant NIA 30378, Georgetown University funding and Merck & Co funds to Charbel E-H Moussa. The authors would like to thank Dr. Jim Driver from the University of Montana for his support in the EM studies.
The authors have read the manuscript and declare no conflict of interest whatsoever.
Dr. Charbel Moussa has a pending application to use nilotinib and bosutinib as a treatment for neurodegenerative diseases. The PCT application number PCT/US13/039283 was filed on May 2, 2013 and claims priority to two provisional patent applications filed on May 2, 2012 and March 1, 2013. The title is “treating neural diseases with tyrosine kinase inhibitors”.
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