‘Undruggable’ Parkinson’s molecule spills its secrets

UC San Francisco researchers have for the first time developed a strategy for targeting a key molecule implicated in Parkinson’s disease, opening up a potential new treatment strategy for the currently incurable movement disorder.

“This molecule is widely regarded as one of the top therapeutic targets for Parkinson’s disease, but this is the first convincing evidence that it can be directly drugged,” said Pamela England, PhD, an associate professor of pharmaceutical chemistry in UCSF’s School of Pharmacy, and of cellular and molecular pharmacology in UCSF’s School of Medicine, who was the senior author of the new study, published March 7, 2019, in Cell Chemical Biology.

Parkinson’s disease affects 10 million people worldwide with progressively worsening movement difficulties as well as cognitive and mood-related symptoms, all of which are caused by degeneration of midbrain neurons that produce the neurotransmitter dopamine. For the vast majority of Parkinson’s patients, their disease has no obvious genetic or environmental cause, and there is currently no treatment to prevent or slow the disease. Existing drugs only temporarily boost dopamine signaling to soften the disease’s symptoms, and can lead to serious side effects.

Over the past decade, research has shown that before dopamine neurons begin to degenerate, they first stop making dopamine, suggesting that defects in the molecular pathway that produces and stores dopamine may be a culprit in the cells’ eventual demise. A prime suspect in this chain of events is the transcription factor Nurr1, a gene-activating protein that is critical for the survival of dopamine neurons, and also regulates many aspects of their dopamine production and storage. Research in genetically modified mice has found that too little Nurr1 can lead to Parkinson-like symptoms, which can be cured by genetically elevating Nurr1 levels.

Researchers have long suspected that boosting Nurr1 with a drug might similarly slow or stop the progression of Parkinson’s disease in humans, and the Michael J. Fox Foundation, which supports Parkinson’s research, has listed it as one of its top five priority targets. But so far, more than a decade of efforts on this front have failed. Unlike other transcription factors, Nurr1 does not have the standard molecular “pocket” that pharmacologists typically look for when designing new drugs, leading some to surmise that nothing naturally binds Nurr1, rendering the molecule “undruggable.”

But England and her team reasoned that for Nurr1 to be able to perform one of its key functions — maintaining proper levels of dopamine in neurons — the molecule must be able to sense unbalanced dopamine levels and restore homeostasis to the system based on some chemical signal. If scientists could identify this signal and replicate it with a drug, it could lead to a new “upstream” approach to boosting dopamine levels in patients with Parkinson’s disease and potentially preventing the cellular damage that triggers dopamine cells to degenerate.

Through extensive testing, including modeling of Nurr1’s structure at the atomic level, England’s team showed that a molecule called DHI, a substance produced when cells dispose of excess dopamine, binds to a previously unsuspected pocket on Nurr1. Further experiments showed that adding DHI to cells in laboratory dishes and in living zebrafish boosted Nurr1 activity, stimulating genes involved in storing and producing dopamine, exactly what pharmacologists have hoped to achieve with a Nurr1-targeting drug.

While DHI itself is too unstable and reactive to be a viable drug candidate, the authors say, the discovery of how it binds to Nurr1 has produced valuable leads for scientists hoping to develop drugs to restore proper dopamine balance in Parkinson’s disease, potentially slowing the progression of the disease.

“We hope these insights will lead to drugs that for the first time can target the underlying causes of Parkinson’s disease,” England said. “But more immediately, this discovery will allow us to better understand Nurr1’s role in the earliest stages of the disease. As always, with understanding comes hope.”

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Authors: The lead author of the new study was John M. Bruning, a graduate student in the UCSF Pharmaceutical Sciences and Pharmacogenomics Graduate Program. Other authors include Yan Wang, Francesca Oltrabella, Boxue Tian, Svetlana A. Kholodar, Harrison Liu, Paulomi Bhattacharya, Su Guo, James M. Holton, Robert J. Fletterick, and Matthew P. Jacobson, all of UCSF.

Funding: The study received early support from the Mary Anne Koda-Kimble Seed Fund, which honors the former dean of the UCSF School of Pharmacy by funding innovative, blue-sky pharmacological research. Additional support was provided by grants from the Rogers Family Foundation, the UCSF Clinical & Translational Science Institute (CTSI), the US National Institutes of Health (R01 NS108404-01), and the UCSF Program for Breakthrough Biomedical Research, which is partially funded by the Sandler Foundation. The research made use of the Advanced Light Source, a national user facility operated by Lawrence Berkeley National Laboratory on behalf of the US Department of Energy under contract number DE-AC02-05CH11231, Office of Basic Energy Sciences.

Disclosures: Jacobson is a consultant to and shareholder of Schrödinger Inc., which develops, licenses, and distributes some of the software used in this work. The other authors declare no competing interests.

About UCSF: UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises three top-ranked hospitals – UCSF Medical Center and UCSF Benioff Children’s Hospitals in San Francisco and Oakland – as well as Langley Porter Psychiatric Hospital and Clinics, UCSF Benioff Children’s Physicians and the UCSF Faculty Practice. UCSF Health has affiliations with hospitals and health organizations throughout the Bay Area. UCSF faculty also provide all physician care at the public Zuckerberg San Francisco General Hospital and Trauma Center, and the SF VA Medical Center. The UCSF Fresno Medical Education Program is a major branch of the University of California, San Francisco’s School of Medicine. Please visit http://www.ucsf.edu/news.

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MEDIA AVAILABLE (Image) Researchers identified a hidden drug target (yellow) on a neuronal protein (blue) that has long been implicated in Parkinson’s disease but was previously considered “undruggable.” (Credit: England lab / UCSF)