Blocking a Key Enzyme Stops Parkinson's Symptoms in Mice Models The image above shows the misfolded alpha-synuclein protein clumping in a neuron in Parkinsonian brain tissue. Researchers at Johns Hopkins say they have gleaned two important new clues in the fight against Parkinson's (PD): that blocking an enzyme called c-Abl prevents the disease in Parkinsonian mice models and that a chemical tag on a second protein may signal the disorder's presence and progression. Autopsies have revealed that c-Abl is especially active in the brains of people with PD and the team took a look at how c-Abl interacts with another protein, α-synuclein. It's long been known that clumps of α-synuclein in the brain are a hallmark of Parkinson's. The Johns Hopkins researchers found that the enzyme c-Abl adds a molecule called a phosphate group to a specific place on α-synuclein, and that increasing levels of c-Abl drove more α-synuclein clumping along with worsening PD symptoms, says Ted Dawson Ph.D, M.D., professor of neurology and director of the Institute for Cell Engineering at the Johns Hopkins University School of Medicine. "There is a Food and Drug Administration-approved c-Abl inhibiting drug in use for leukemia*," Dawson states, "so we're interested in whether it could be used safely against Parkinson's disease or as a starting point to develop other treatments." Studies in mice bred to be prone to the disease found drugs that block c-Abl may prevent or slow it. But, says Han Seok Ko, Ph.D., assistant professor of neurology at Johns Hopkins, "the drugs used in those studies could also have been blocking similar proteins, so it wasn't clear that blocking c-Abl was what benefited the animals by either preventing symptoms or influencing disease progression."The researchers' new experiments started with mice genetically engineered to develop the disease and "knocked out" the gene for c-Abl, a move that reduced their disease symptoms. Conversely, genetically dialing up the amount of c-Abl the mice produced worsened symptoms and hastened the disease's progression. Increasing c-Abl production also caused normal mice to develop Parkinson's disease, the researchers say. "We plan to look into whether α-synuclein with a phosphate group on the spot c-Abl targets could serve as a measure of PD severity," he says. No such objective, biochemical measurement exists now, he notes, which hampers studies of potential therapies for the disease. Dawson and Ko caution that the use of the anti-leukemia drug *Nilotinib is not yet indicated for PD patients and that further studies are needed before their results can be applied to clinical care. Note: *For the last few years our LCT committee has explored whether inhibition of cAbl by Nilotinib would offer a disease-modifying approach for PD and based on compelling biochemical evidence and considerable discussion, this expert committee concluded that the use of Nilotinib had 'significant potential to slow neurodegeneration in PD'. Please refer to our Trials Pending section for further information and updates. Full report: Saurav Brahmachari et al, Activation of tyrosine kinase c-Abl contributes to α-synuclein–induced neurodegeneration, Journal of Clinical Investigation (2016). DOI: 10.1172/JCI85456 Read the full online article in Medical Xpress.