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Join Date: Nov 2006
Location: southern tip of west coast
Posts: 582
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Member
Join Date: Nov 2006
Location: southern tip of west coast
Posts: 582
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Mechanism of Nilotinib (animal study)
Use of Nilotinib Cancer Drug for Treatment of Parkinson’s, Alzheimer’s, Dementia
Hum. Mol. Genet. (2013)doi: 10.1093/hmg/ddt192 First published online: May 10, 2013
Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of α-synuclein in Parkinson’s disease models
Michaeline L. Hebron†, Irina Lonskaya† and Charbel E.-H. Moussa
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.
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