NEW YORK, NY — The Michael J. Fox Foundation for Parkinson’s Research today announced $3.5 million in total funding to nine research studies aiming to advance understanding of the LRRK2 gene, a promising therapeutic target for Parkinson’s disease. Using a multipronged approach that includes collaboration between the research teams, the funded projects will help accelerate LRRK2 therapeutic development efforts.
First linked to Parkinson’s disease in 2004, the LRRK2 gene is now believed to be the most common genetic contributor to the disease. Recent evidence also suggests that genetic variation in LRRK2 may be involved in the more common, sporadic form of PD. For these reasons, MJFF has identified LRRK2 as a high-priority therapeutic target, investing nearly $17 million to date for a broad and integrated strategy to drive critical LRRK2-related initiatives at every stage of drug development.
The studies announced today are part of this broader effort. The researchers will help elucidate the role of LRRK2 in PD, which is only partially understood, by investigating the functions of LRRK2 in the cell; identifying other cellular proteins linked to LRRK2 (called ‘substrates’) as potential new sources of therapeutic targets; and developing tools and technologies to drive further research on LRRK2. The nine research teams will also form a LRRK2 consortium, sharing results and collaborating with each other to tackle problems as they arise.
To refine understanding of LRRK2, four research teams are investigating the functions of LRRK2 in the cell. One team led by David S. Park, PhD of the University of Ottawa is using three complementary approaches to define the interacting partners and molecular pathways of LRRK2, characterizing these functions in fruit flies, mammalian preclinical models and, finally, human tissues.
The three teams funded to investigate LRRK2 substrates are also using a variety of tissue sources, improving the ability of these researchers to cross-validate any findings. A multidisciplinary team led by Shu G. Chen, PhD of Case Western Reserve University School of Medicine is working with cellular models of PD to identify LRRK2 substrates, whereas another team led by Darren J. Moore, PhD of Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne in Switzerland is focusing his work in animal models. As part of his group’s investigation into LRRK2 substrates, Patrick A. Lewis, PhD of the University College London Institute of Neurology is comparing tissues from people with PD who carry LRRK2 mutations to tissues from people who do not have these mutations.
The remaining two teams are developing tools to help researchers characterize LRRK2 and develop therapies that are specific to this genetic target. To date, the large size and complexity of the LRRK2 protein has hindered the ability of researchers to produce highly pure and active LRRK2 for use in biochemical experiments. Elisa Greggio, PhD of the University of Padova, is using genetically engineered viral vectors to ‘trick’ cells into making LRRK2, hoping to produce pure and functional LRRK2 to help advance drug development efforts. Both Dr. Greggio’s team as well as a second team from the company Life Technologies will also develop methods to produce a related protein, LRRK1, studies of which could provide critical insight into the function of LRRK2.
In addition to the $3.5 million for the nine research studies announced today, MJFF has also recently awarded $500,000 under a separate LRRK2 project. This award will help to coordinate previously announced efforts to study PD patients with the LRRK2 mutation.
The following is a complete list of funded projects, which are made possible through the generous support of The Brin Wojcicki Foundation. Grant abstracts and researcher bios are available on the Foundation’s Web site, www.michaeljfox.org.
Characterization of LRRK2 Cellular and Signaling Pathways
Shu G. Chen, PhD, Case Western Reserve University School of Medicine
Biochemical Characterization of Full Length Human Recombinant LRRK1 and LRRK2
Elisa Greggio, PhD, University of Padova
LRRK2 in Neuronal Architecture
Matthew Farrer, PhD, Mayo Clinic Jacksonville
Investigating Signaling Dysfunction Linked to LRRK2
Patrick A. Lewis, PhD, University College London Institute of Neurology
LRRK2 Mediated Pathogenic Pathways in Dopaminergic Axonal Degeneration and Synaptic Transmission
Wencheng Liu, PhD, Weill Medical College of Cornell University
Identification of LRRK2 Substrates in Mouse Models of Parkinson’s Disease
Darren J. Moore, PhD, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne
Functional Analysis of LRRK2
David S. Park, PhD, University of Ottawa
Elucidating the Function and Downstream Targets of LRRK2
John Dunlop, PhD, Pfizer
Zhenyu Yue, PhD, Mt. Sinai School of Medicine
Development of Biochemical Assays for LRRK1
Steven M. Riddle, Life Technologies (Invitrogen)
Building a LRRK2 Cohort Core Database (additional $500,000 award)
Cynthia J. Casaceli, MBA, University of Rochester Medical Center