title: Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of α-synuclein in Parkinson's disease models.
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.
authors.affiliation: Department of Neuroscience, Laboratory for Dementia and Parkinsonism, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Michaeline L
authors.initials: ML
authors.lastname: Hebron
authors.forename: Irina
authors.initials: I
authors.lastname: Lonskaya
authors.forename: Charbel E-H
authors.initials: CE
authors.lastname: Moussa
mesh_terms: D000328:Adult; D000818:Animals; D001343:Autophagy; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000502:physiology; D016313:Genes, abl; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D013378:Substantia Nigra / Q000378:metabolism; D051844:alpha-Synuclein / Q000097:blood / Q000378:metabolism*
chemical_list: D011743:Pyrimidines; D051844:alpha-Synuclein; D016315:Proto-Oncogene Proteins c-abl; C498826:nilotinib; D004298:Dopamine