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.
Highlights
Striatal dopamine deficiency caused by the degenerative loss of nigral dopaminergic cells is the main pathological feature of Parkinson’s disease (PD; Olanow and Tatton, 1999)
Striatal levels of Cdk5pTyr15 (Figure 2A; P < 0.05, analysis of variance (ANOVA)) and DARPP-32-pThr75 (Figure 2B; P < 0.05, ANOVA) were significantly reduced in mice injected with nilotinib at the doses of 25 and 50 mg/kg, compared to mice treated with vehicle
Systemic administration of nilotinib could inhibit striatal phosphorylation of both cyclin-dependent kinase 5 (Cdk5) at Tyr15, the substrate site targeted by c-Abelson tyrosine kinase (c-Abl) (Zukerberg et al, 2000; Dhavan and Tsai, 2001; Zhang et al, 2007), and DARPP-32 at Thr75, the substrate site targeted by Cdk5 (Greengard, 2001), in naïve mice
Summary
Striatal dopamine deficiency caused by the degenerative loss of nigral dopaminergic cells is the main pathological feature of Parkinson’s disease (PD; Olanow and Tatton, 1999). Corticostriatal glutamate inputs activate cyclin-dependent kinase 5 (Cdk5), which inhibits postsynaptic dopamine signaling by phosphorylating DARPP-32 at Thr (Thr75-DARPP-32) in the striatum (for reference, see Figure 1). In rodent models of PD, striatal dopamine deficiency has been shown to have no effect on phosphorylation of Thr34-DARPP-32, but significantly increase that of Thr75-DARPP-32 (Brown et al, 2005; Santini et al, 2007). These findings suggest that the glutamate/Cdk5/DARPP32-pThr pathway might be important in assessing the molecular mechanisms underlying PD symptoms
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