Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of α-synuclein in Parkinson's disease models
Authors: Michaeline L Hebron
Charbel E-H Moussa
Irina Lonskaya
Journal: Human Molecular Genetics (2013)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Parkinson's disease; dopaminergic neurons; α-synuclein; tyrosine kinase Abl; neurodegeneration
Affiliations: Department of Neuroscience, Laboratory for Dementia and Parkinsonism, Georgetown University Medical Center, Washington, DC 20057, USA.

Abstract:  Parkinson's disease is a movement disorder characterized by death of dopaminergic substantia nigra (SN) neurons and brain accumulation of α-synuclein. The tyrosine kinase Abl is activated in neurodegeneration. Here, we show that lentiviral expression of α-synuclein in the mouse SN leads to Abl activation (phosphorylation) and lentiviral Abl expression increases α-synuclein levels, in agreement with Abl activation in PD brains. Administration of the tyrosine kinase inhibitor nilotinib decreases Abl activity and ameliorates autophagic clearance of α-synuclein in transgenic and lentiviral gene transfer models. Subcellular fractionation shows accumulation of α-synuclein and hyper-phosphorylated Tau (p-Tau) in autophagic vacuoles in α-synuclein expressing brains, but nilotinib enhances protein deposition into the lysosomes. Nilotinib is used for adult leukemia treatment and it enters the brain within US Food and Drug Administration approved doses, leading to autophagic degradation of α-synuclein, protection of SN neurons and amelioration of motor performance. These data suggest that nilotinib may be a therapeutic strategy to degrade α-synuclein in PD and other α-synucleinopathies. 

Retracted: No

PubPeer comments:
 Concern about Figure 3. * Red boxes: Panels C and D, displaying with or without Nilotinib treatment, appear to overlap. ![file] , 
 Concern about Figure 5. * Blue boxes: Panels G ( lentiviral LacZ injected with nilotinib) and I (Lentiviral a-synuclein treated with nilotinib) appear to overlap. ![file] , 
 There are additional concerns about images that overlap with that of another paper from the same group. ![file] , 
 #1 I thank the reviewer for the comment. The e-mails have for some reason been going to Junk mail. I apologize for the late reply. Tyrosine hydroxylase+cell staining may look similar in different animals, but an error may have happened by the authors when they tiled the final images or panels and this is regrettable. However, these figures, show multiple animals and low and high magnification. , 
 Additional concerns about panels which overlap with other papers from the same group. ![file] , 
 Further concerns of overlap with other papers from the same group.![file] , 
 #3 Please see response to figures that were submitted as a correction to the journal. We apologize for the errors in tiling the digital figures. Please see attached. ![file] ![file] , 
 #6 We will inspect these images to make sure that there is no error in Fig 4 of Lonskaya et al 2013. Unfortunately, different investigators used the same template to tile and generate images for publication as these images would have the same size and fit the slides for composite images. , 
 #5 This work was done by different people at the same time (i.e. someone examined protein changes and another person re-run the gels and performed quantification), but as the digital templates were used by all authors, certain blots may have erroneously been left by some investigators and loading controls were assigned to the wrong blots. The person who performed the quantification was the same and may have overlooked the loading controls on the final manuscript s. We will investigate and respond accordingly. , 
 #5 ![file] , 
 #6 Please see corrected figures. We thank you for detecting these errors that are quite frustrating and embarrassing. We will submit a correction to the journal. ![file] , 
 #5 #4 Please see correction sent to journal. ,