Researchers at the university's
for Cell Engineering have discovered a protein that
could be the best new target in the fight against
Parkinson's disease since the brain-damaging condition was
first tied to loss of the brain chemical dopamine.
Over the past year, the gene for this protein, called
LRRK2 (pronounced "lark-2"), had emerged as perhaps the
most common genetic cause of both familial and
unpredictable cases of Parkinson's disease. Until now,
however, no one knew for sure what the LRRK2 protein did in
brain cells or whether interfering with it would be
Now, after studying the protein in the lab, the Johns
Hopkins researchers report that the huge LRRK2 protein is
part of a class of proteins called kinases and, like other
members of the family, helps control other proteins'
activities by transferring small groups called phosphates
onto them. The researchers also report that two of the
known Parkinson's-linked mutations in the LRRK2 gene
increase the protein's phosphate-adding activity. The
findings appear in the Nov. 15 issue of the Proceedings
of the National Academy of Sciences.
"We know that small molecules can interfere with this
kind of activity, so LRRK2 is an obvious target for drug
development," said Ted Dawson, co-director of the Neural
Regeneration and Repair Program within ICE and a leader of
the study. "This discovery is going to have a major impact
on the field. It's going to get people talking about kinase
Because kinases affect a number of other proteins,
LRRK2's link to Parkinson's may be a result of either its
own activity or a shift in the activities of one or more
"The next step is to prove that LRRK2 overactivity
results in the death of brain cells that produce dopamine,
the defining pathology of Parkinson's disease, and to
figure out how it does so," said Dawson, who cautions that
the large size of the LRRK2 gene and protein could make
clinical application of the Hopkins discovery years
"For example, we would want to isolate the active part
of the LRRK2 protein and use that more manageable part to
screen for molecules that would block its activity. But
what takes us a second to think of could take four or five
months to do," Dawson said. "These things may not come as
fast as the field wants."
The LRRK2 protein, sometimes called dardarin, is 2,527
building blocks long. In contrast, the alpha-synuclein
protein, the first to be linked to Parkinson's disease, is
only 140 building blocks long. The parkin protein, linked
to more cases of familial Parkinson's disease than any
other to date (although LRRK2 is likely to break that
record), is considered "big" at 465 building blocks
Undaunted by the size of the LRRK2 gene and protein,
Andrew West, a postdoctoral fellow and co-first author of
the paper, spent months extracting the full-length gene
from human brain samples and developing reliable
experiments to test how mutations affected LRRK2's
activity. Co-first author Darren Moore, also a postdoctoral
fellow, built the tools to get bacteria to make mounds of
LRRK2 protein and two mutant versions and also tracked down
the LRRK2 protein's location inside cells.
The research team's experiments showed that the LRRK2
protein, in addition to its role as a kinase, actually sits
on mitochondria, cells' energy-producing factories, where
it likely interacts with a complex of proteins whose
failure has also been implicated in Parkinson's disease.
Mutations in LRRK2 were first tied to Parkinson's
disease in 2004 and to date explain perhaps 5 percent to 6
percent of familial Parkinson's disease (specifically
so-called autosomal dominant cases, in which inheriting a
single faulty copy of the gene results in disease) and
roughly 1 percent of Parkinson's disease in which there is
no family history. But few of the gene's genetic regions
have been analyzed in depth.
"As researchers comb through the rest of the LRRK2
gene, it seems likely that more mutations will be found and
that [the gene] will be tied to more varieties of the
disease," Dawson said.
What's known about LRRK2 so far suggests that it might
connect diseases long thought to be distinct, particularly
Parkinson's disease and conditions known as "diffuse Lewy
body disease," named for the bundles of certain proteins
that build up inside cells in the brain in affected people.
As a result, studying LRRK2 might improve understanding of
and eventually treatment for more than just Parkinson's
disease itself, Dawson says.
The research was funded by the National Institute of
Neurological Disorders and Stroke, Lee Martin Trust, Sylvia
Nachlas Trust, National Parkinson Foundation and American
Parkinson's Disease Association.
Authors on the paper, in addition to West and Dawson,
are Darren Moore, Saskia Biskup, Artem Bugayenko, Wanli
Smith, Christopher Ross and Valina Dawson, all of Johns
Hopkins. Valina Dawson is co-director of the Program in
Neuroregeneration and Repair of the Institute for Cell
Engineering at Johns Hopkins.