Inhibition of c-Abl Tyrosine Kinase as a Novel Therapy to Prevent PD Progression

Objective/Rationale:              Mutations in the parkin gene cause early-onset autosomal recessive PD. We have discovered that parkin is modified by an oxidative-stress induced signaling kinase, c-Abl, resulting in loss of parkin’s protective functions. This modification of parkin leads to the accumulation of toxic intermediates that can cause the dopaminergic neurons to die, and thus facilitate the progression of PD. Our central hypothesis is that stress-induced, Abl-mediated, tyrosine phosphorylation of parkin is a novel mechanism contributing to the pathogenesis of sporadic PD, and that inhibition of c-Abl activity offers a novel approach to the amelioration of PD progression.   Project Description:               We will evaluate the inhibition of c-Abl tyrosine kinase by NS-187 (Innovive, New York) as a possible therapeutic target for reducing the progressive neuronal loss during PD by maintaining parkin in a non-phosphorylated and catalytically active state in experimental models of PD such as midbrain dopaminergic neurons and the brains of mice exposed to dopaminergic toxin MPTP. We will employ molecular biological (protein function of parkin, activation of c-Abl), neurochemical (loss of dopamine, levels of oxidative stress, solubility of proteins such as parkin, accumulation of toxic substrates of parkin) and neuropathological (loss of tyrosine hydroxylase positive neurons) endpoints to analyze if c-Abl inhibition in these experimental models maintains the function and integrity of nigrostriatal system, an area affected during PD.   Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     The use of c-Abl inhibitors might become an effective therapy to prevent dopaminergic cell loss during PD pathogenesis and may reduce the loss of PARKIN function, reduce apoptotic neuronal death, and inhibit the progression of PD. In future, assays of activation of c-Abl in the lymphocytic cells of blood, which express the kinase at high levels, may be useful as a readily accessible early-diagnosis biomarker for individuals who are at high risk for PD.   Anticipated Outcome:            Results will provide insights into the role of tyrosine phosphorylation of parkin as a pathogenic mechanism in PD progression and provide structural and biochemical basis for new approach to therapy of PD. The results will at least establish a body of reliable evidence upon which future interventional protocols can be based. Ultimately, the effect of c-Abl inhibitors on PD progression will have to be tested on PD patients, but this will depend upon the data obtained from the animals studies described here.