The majority of Parkinson’s disease (PD) cases have no known cause, but have been associated with increased oxidative stress and mitochondrial dysfunction. Of the small proportion of hereditary cases, a number of defective genes have been identified including LRRK2 (PARK8), DJ-1 (PARK7), α-synuclein (SNCA) and parkin (PARK2). Mutations in parkin, which encodes an E3 ubiquitin ligase, are believed to interfere with the ability of parkin to clear the cell of its normal substrate proteins. Several substrates for parkin have been identified and shown to accumulate in the brain tissue of patients with hereditary PD.
Researchers at The University of Texas Health Science Center have now identified a link between the tyrosine kinase, c-Abl, and impaired parkin function. The scientists found that c-Abl was activated in cultured neuronal cells and the striatum of adult mice when subjected to oxidative and neuronal stress. They also identified parkin as a specific substrate for c-Abl and that the tyrosine-phosphorylated parkin lost its ubiquitin ligase activity.
The c-Abl inhibitor, imatinib (STI-571) was able to block the phosphorylation of parkin in vitro and in vivo, restoring ligase activity. Since there are several c-Abl inhibitors approved for the treatment of chronic myelogenous leukemia, tools are available to further explore the neuroprotective potential of c-Abl inhibition in sporadic PD.
The study is published in the Journal of Neuroscience.
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