June 27, 2016
Researchers at Johns Hopkins say
they have gleaned two important new clues in the fight against Parkinson's
disease: that blocking an enzyme called c-Abl prevents the disease in specially
bred mice, and that a chemical tag on a second protein may signal the
disorder's presence and progression. Their work, described online June 27 in The
Journal of Clinical Investigation, suggests both a promising target for
drug research and a tool that could speed Parkinson's disease research more
broadly, they say.
"There were indications that
c-Abl activity leads to Parkinson's disease, and our experiments show there is
indeed a connection," says Ted Dawson, M.D., Ph.D., professor of neurology
and director of the Institute for Cell Engineering at the Johns Hopkins
University School of Medicine. "There is already a Food and Drug
Administration-approved c-Abl inhibiting drug in use for leukemia," he
adds, "so we're interested in whether it could be used safely against
Parkinson's disease or as a starting point to develop other treatments."
Autopsies have revealed that c-Abl
is especially active in the brains of people with Parkinson's disease, a
progressive disorder of the nervous system that affects movement. Additionally,
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.
To learn more about how that
happened, 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 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
symptoms, says Dawson.
"We plan to look into whether
α-synuclein with a phosphate group on the spot c-Abl targets could serve as a
measure of Parkinson's disease 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 Parkinson's
disease patients and that further studies are needed before their results can
be applied to clinical care.
About 60,000 Americans are
diagnosed with Parkinson's disease each year, and up to 10 million people
worldwide are living with the disease, according to the Parkinson's Disease
Foundation.
People with the disease commonly experience tremors; slow, stiff
movement; mood disorders; sleep disorders; and other symptoms. Certain gene variants
and environmental exposures have been linked to Parkinson's disease, though its
causes are still under investigation.
More information: 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
Journal reference: Journal of
Clinical Investigation 
Provided by: Johns Hopkins
University School of Medicine
http://medicalxpress.com/news/2016-06-protein-alpha-synuclein-aggregation-parkinson-disease.html?
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