title: Tyrosine kinase inhibition facilitates autophagic SNCA/α-synuclein clearance.
abstract: The effects of ABL1/ABL inhibition on clearance of SNCA/α-synuclein were evaluated in animal models of α-synucleinopathies. Parkinson disease (PD) is a movement disorder characterized by death of dopaminergic substantia nigra (SN) neurons and brain accumulation of SNCA. The tyrosine kinase ABL1 is activated in several neurodegenerative diseases. An increase in ABL1 activity is detected in human postmortem PD brains. Lentiviral expression of SNCA in the mouse SN activates ABL1 via phosphorylation, while lentiviral Abl expression increases SNCA levels. Administration of the brain-penetrant tyrosine kinase inhibitor Nilotinib decreases Abl activity and facilitates autophagic clearance of SNCA in transgenic and lentiviral gene transfer models. Subcellular fractionation demonstrates accumulation of SNCA and hyperphosphorylated MAPT/Tau (p-MAPT) in autophagic vacuoles in SNCA-expressing brains, while Nilotinib treatment leads to protein deposition into the lysosomes, suggesting enhanced autophagic clearance. These data suggest that Nilotinib may be a therapeutic strategy to degrade SNCA in PD and other α-synucleinopathies.
authors.affiliation: Department of Neuroscience; Laboratory for Dementia and Parkinsonism; Georgetown University Medical Center; Washington DC, 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: D000818:Animals; D001343:Autophagy; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects*; D006801:Humans; D008297:Male; D020734:Parkinsonian Disorders / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D011743:Pyrimidines; D051844:alpha-Synuclein; D004298:Dopamine
keywords: Nilotinib; Tau; autophagy; dopamine; Î±-synuclein