A novel tyrosine kinase inhibitor AMN107 (nilotinib) normalizes striatal motor behaviors in a mouse model of Parkinson’s disease

Abstract

Abnormal motor behaviors in Parkinson’s disease (PD) result from striatal dysfunction due to an imbalance between dopamine and glutamate transmissions that are integrated by dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). c-Abelson tyrosine kinase (c-Abl) phosphorylates cyclin-dependent kinase 5 (Cdk5) at Tyr15 to increase the activity of Cdk5, which reduces the efficacy of dopaminergic signaling by phosphorylating DARPP-32 at Thr75 in the striatum. Here, we report that in the mouse striatum, a novel c-Abl inhibitor, nilotinib (AMN107), inhibits phosphorylation of both Cdk5 at Tyr15 and DARPP-32 at Thr75, which is negatively regulated by dopamine receptor activation through a D2 receptor-mediated mechanism. Like a D2-agonist, nilotinib synergizes with a D1-agonist for inducing striatal c-Fos expression. Moreover, systemic administration of nilotinib normalizes striatal motor behaviors in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. These findings suggest that nilotinib could possibly serve as a new and alternative agent for treating PD motor symptoms.

STEP61is a substrate of the E3 ligase parkin and is upregulated in Parkinson’s disease

“…Here we demonstrate that parkin is an E3 ligase for STEP 61 (striatalenriched protein tyrosine phosphatase), a protein tyrosine phosphatase implicated in several neuropsychiatric disorders. In cellular models, parkin ubiquitinates STEP 61 and thereby regulates its level through the proteasome system, whereas clinically relevant parkin mutants fail to do so.…”

“…In cellular models, parkin ubiquitinates STEP 61 and thereby regulates its level through the proteasome system, whereas clinically relevant parkin mutants fail to do so. STEP 61 protein levels are elevated on acute down-regulation of parkin or in PARK2 KO rat striatum.…”

Activation of tyrosine kinase c-Abl contributes to α-synuclein–induced neurodegeneration

“…Inhibition of c-Abl may also be protective by inhibiting p38α (52). In addition, c-Abl inhibition may also have symptomatic effects as it normalizes striatal motor behaviors in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD (53). Future studies are indicated to determine the major pathway by which c-Abl inhibition provides neuroprotection.…”

“…Previous studies indicate that brain-penetrant c-Abl inhibitors protect against MPTP neurotoxicity (26,48) and normalize striatal motor behaviors (53), as well as reverse the loss of DA neurons and improve motor behavior in a viral α-synuclein model of PD (25). However, a major caveat of these reports is that the inhibitors is the first report showing that phosphotyrosine 39 α-synuclein is elevated in the substantia nigra and striatum of PD postmortem brains and that it accumulates in the Lewy bodies.…”

Multifunctional Abl kinases in health and disease

“…Abl kinases also phosphorylate Cdk5 on tyrosine residue 15, which contributes to cell death through the activation of p53 (Lee et al, 2008;Li, 2005) and reduces dopaminergic signaling through phosphorylation of DARPP-32 (also known as PPP1R1B), an important target for dopamine and protein kinase A in the striatum (Tanabe et al, 2014). Treatment of mice with nilotinib in mouse models of Parkinson's disease decreased the loss of dopaminergic neurons, and reduced behavioral deficits and motor symptoms (Karuppagounder et al, 2014;Tanabe et al, 2014).…”