Alpha-Synuclein

The Michael J. Fox Foundation for Parkinson’s Research

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A recently published study funded by The Michael J. Fox Foundation and using MJFF research tools showed two avenues through which inhibiting the function of the protein LRRK2 may help treat Parkinson’s. The paper from the laboratory led by Andrew West, PhD, from the University of Alabama at Birmingham, appears in the Proceedings of the National Academy of Sciences.

Mutations in the LRRK2 gene are the greatest known genetic cause of PD, accounting for one to two percent of all cases of PD and more in certain ethnic populations. Mutations appear to heighten activity of the LRRK2 protein. Therefore, development of LRRK2 inhibitors is a priority of the Foundation.

“LRRK2 is one of our most promising areas of research toward a therapy to stop or slow the progression of Parkinson’s, and MJFF has established a roadmap to learn more about this target and build the infrastructure to accelerate discovery and drug development,” said Marco Baptista, PhD, MJFF associate director of research programs.

Part of the Foundation’s LRRK2 roadmap is the creation of research tools such as pre-clinical models and antibodies important to hasten the development of future therapeutics. The LRRK2 knockout pre-clinical model is bred without the LRRK2 gene, which can mimic the effects of a LRRK2 inhibitor drug.

Dr. West and his team studied both the LRRK2 knockout model and a wild-type model (typical form) when they introduced an excess of the protein alpha-synuclein. Parkinson’s is marked by clumps of alpha-synuclein in brain cells, which leads to cell death. The scientists compared the effects of too much alpha-synuclein in a LRRK2 knockout and a control model.

They found cell loss from the excess alpha-synuclein in the wild-type model but not in the LRRK2 knockout, meaning inhibiting LRRK2 could protect from neurodegeneration.

Using new antibodies developed by MJFF, Dr. West also found that LRRK2 was highly expressed in cells that responded to injury, leading to another hypothesis that inhibiting LRRK2 may help alleviate a specific type of inflammation. To test this hypothesis, they also introduced an inflammatory agent into both models and found, again, that the wild-type model experienced cell loss while the LRRK2 knockout did not.

Often tests of LRRK2 inhibitors use models with LRRK2 gene mutations. Since this study compared only knockout and wild-type models, its findings suggest LRRK2 inhibition may also benefit people who have PD but no LRRK2 mutations (the majority of PD patients).

“This broadens the window of those who might be helped by this therapeutic approach beyond only those with a LRRK2 mutation,” said Dr. West. “Seeing protection in this study gave us the green light to attempt and copy the symptomatic results pharmacologically, to help find a drug that we can bring to clinical trial.”

He is working on testing LRRK2 inhibitors, through separate projects with the Alabama Drug Discovery Alliance and with Pfizer. MJFF is funding the collaborative project with Pfizer.

 

More Alpha-Synuclein in Spinal Fluid Linked to Faster Cognitive Decline

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Alpha-synuclein — the protein that clumps in the cells of Parkinson’s patients — is currently the major focus of Parkinson’s biomarker studies. Researchers are analyzing biosamples (spinal fluid, blood, tissue) to make a connection between alpha-synuclein and risk, onset or progression of Parkinson’s disease (PD). The latest findings, published in The American Journal of Pathology, report that patients with higher levels in spinal fluid experienced faster cognitive decline.

In a project funded by The Michael J. Fox Foundation (MJFF), Jing Zhang, MD, PhD, and his team at the University of Washington in Seattle examined samples and data from PD patients obtained in the DATATOP study. Led by the Parkinson’s Study Group in the late 1980s, the deprenyl and tocopherol antioxidative therapy of parkinsonism (DATATOP) study collected samples and clinical data from PD subjects for up to eight years.

In this latest analysis, researchers compared alpha-synuclein levels to scores from tests of cognition, such as verbal learning and memory, visuospatial memory and processing speed, among 304 PD patients. They found that patients with higher levels of alpha-synuclein in spinal fluid had faster cognitive decline.

“This is a surprising conclusion,” says Mark Frasier, PhD, MJFF vice president of research programs. “One would think that people with more cognitive problems would have less alpha-synuclein in spinal fluid because more would be caught up in the brain causing those problems.”

Zhang’s group also reported that while alpha-synuclein levels decreased significantly over two years, that decline could not predict motor symptoms. These findings join a list of observations about how alpha-synuclein in spinal fluid relates to PD. Initial analysis from the MJFF-sponsored Parkinson’s Progression Markers Initiative (PPMI) reported last year that PD patients had lower alpha-synuclein levels in spinal fluid compared to controls. They also found that patients with posture/gait disturbance averaged lower alpha-synuclein than patients with tremor-dominant PD.

Further investigation into alpha-synuclein continues in PPMI and other studies. Zhang and his coauthors cited PPMI as a potential source for validation of their cognition findings. Since PPMI includes healthy controls, researchers could test whether those results are PD-specific or seen in healthy aging adults with cognitive decline, too.

To accelerate research around PD biomarkers, MJFF spearheaded an effort to make data and samples from varied Parkinson’s studies available to investigators. The Foundation also offers funding to use the data and samples, such as to Zhang for the DATATOP analysis.