Magdalena Kegel
Researchers at Johns Hopkins University School of Medicine have discovered that an enzyme known to be highly active in the brains of Parkinson’s disease patients places a molecular tag on the protein α-synuclein, causing it to aggregate and worsen its symptoms.
The study, “Activation of tyrosine kinase c-Abl contributes to α-synuclein–induced neurodegeneration,” which appeared in The Journal of Clinical Investigation, showed researchers a key process triggering Parkinson’s — which might be blocked with existing drugs to stop disease progression.
The formation of so-called α-synuclein fibrils — insoluble structures that clump to form Lewy bodies — is a hallmark of Parkinson’s disease. So far, little has been known about the forces starting the process of aggregation.
While earlier studies have hinted at the possibility that the enzyme, called c-Abl, might be involved in Parkinson’s disease, animal experiments have not delivered straightforward answers. Treating mice with drugs blocking c-Abl prevented disease progression, but the drugs also block other enzymes, making it impossible to know if the beneficial effects were linked to c-Abl.
To get around this problem, scientists removed the gene coding for the enzyme in a mouse bred to develop Parkinson’s features. This reduced both α-synuclein aggregation and improved symptoms of the disease.
When scientists reversed the experiment by instead triggering overproduction of the enzyme, protein aggregation accelerated, causing more brain toxicity and worsening symptoms, with a more rapid disease progression. When c-Abl activity was boosted in normal mice with no inclination for disease, they also developed Parkinson’s.
Zooming in on the molecular actions of the enzyme provided researchers with an explanation. They discovered that c-Abl placed a molecular tag on α-synuclein. Such tags are used by the body to either activate, deactivate, or change the function of a protein, much like an on/off switch or mode button on your audio device.
In the current study, researchers could observe that higher levels of the enzyme corresponded to a faster rate of α-synuclein aggregation, prompting the idea to use flagged α-synuclein as an objective marker of Parkinson’s severity — a possibility that would greatly aid the development of new drugs.
Ted Dawson, a professor of neurology and director of the Institute for Cell Engineering at Johns Hopkins who led the study along with Dr. Han Seok Ko, noted that shortcuts might exist for drug development purposes.
“There is already a Food and Drug Administration-approved c-Abl inhibiting drug in use for leukemia,” Dawson said, “so we’re interested in whether it could be used safely against Parkinson’s disease or as a starting point to develop other treatments.”
Both Dawson and Ko, however, caution against using the leukemia drug in Parkinson’s patients before adequate testing confirms that it is safe.
http://parkinsonsnewstoday.com/2016/06/29/enzyme-triggering-parkinsons-protein-aggregation-might-be-key-to-halting-disease/
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