Parkinson's researchers used proteomics to
identify Rab proteins as a physiological substrate of LRRK2, a
Parkinson's drug target. This finding may accelerate current research
and open a novel therapeutic avenue.
Credit: MPI of Biochemistry
An international public-private research
consortium has identified and validated a cellular role of a primary
Parkinson's disease drug target, the LRRK2 kinase. This important
finding, published in the online, open-access eLife journal,
illuminates a novel route for therapeutic development and intervention
testing for Parkinson's, the second most common neurodegenerative
disease after Alzheimer's.
A team of investigators from the Max Planck Institute of
Biochemistry, the University of Dundee, The Michael J. Fox Foundation
for Parkinson's Research (MJFF), GlaxoSmithKline (GSK) and MSD
contributed unique tools and expertise toward rigorous systematic
testing that determined the LRRK2 kinase regulates cellular trafficking
by deactivating certain Rab proteins (3, 8, 10 and 12).
Mutations in the LRRK2 gene are the greatest known genetic
contributor to Parkinson's disease. Pharmaceutical companies are
developing LRRK2 kinase inhibitors to correct the effects of those
mutations and treat Parkinson's disease. This new breakthrough finding
that links mutant LRRK2 to inappropriate deactivation of Rab function
unlocks more than 20 years of accumulated knowledge of the roles of Rab
proteins. This knowledge can now be integrated to significantly improve
our understanding of LRRK2 dysfunction in the Parkinson's disease
process.
"The pathological cascade leading to brain diseases such as
Parkinson's likely includes many cellular players," said Matthias Mann,
PhD, Director of the Department of Proteomics and Signal Transduction at
the Max Planck Institute of Biochemistry. "The identification of this
LRRK2 substrate gives us a central piece in this puzzle and another
potential place to intervene in the disease process."
Marco Baptista, PhD, MJFF Senior Associate Director of Research
Programs, said, "Identification of Rab proteins as a LRRK2 substrate
presents a tool to measure the impact of these inhibitors not only on
LRRK2 levels but also on LRRK2 function. This critical component will
advance development of these therapies to slow or stop Parkinson's
disease, patients' greatest unmet need."
This MJFF-led consortium used a combination of tools in the
discovery, including a knock-in mouse model of the most common LRRK2
mutation strongly associated with Parkinson's (created by GSK), a second
knock-in LRRK2 mouse model generated by MJFF, LRRK2 kinase inhibitors
from GSK and Merck, and state-of-the-art mass spectrometry. These tools
-- and the collaborative spirit that united the partners -- were
necessary to make this finding.
"This unique model of collaboration and our systematic approach
across laboratories using advanced technologies and layers of
confirmation provide a firm foundation from which to continue this line
of investigation and further refine our understanding of the LRRK2 Rab
relationship," said Dario Alessi, PhD, Director of the Protein
Phosphorylation and Ubiquitylation Unit at the University of Dundee.
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