Nilotinib reverses loss of dopamine neurons and improvesmotorbehavior via autophagic degradation of α-synuclein in parkinson's disease models

Abstract

Parkinson's disease is amovement 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 showthat lentiviral expression ofα-synuclein in themouseSNleads to Abl activation (phosphorylation)and lentiviral Abl expression increasesα-synuclein levels, inagreement withAbl activation inPDbrains.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 fractionationshows accumulation ofα-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. © The Author 2013. Published by Oxford University Press. All rights reserved.