Mount Sinai Study Suggests Vitamin B12 May Be Potential Antidote to LRRK2-Associated Parkinson’s Disease
Findings could help inform development of new LRRK2-based therapeutic agents
The basic micronutrient vitamin B12 inhibits the activity of a protein implicated in LRRK2-associated Parkinson’s disease (PD) the most common inherited form of the condition, according to research conducted at the Icahn School of Medicine at Mount Sinai and published March 11 in the journal Cell Research. The study findings suggest that vitamin B12 may hold promise as a PD therapy.
Parkinson’s disease, the most common chronic neurodegenerative disorder, affects one percent of the world population over the age of 60 by disabling the brain and disrupting both motor and cognitive function. Missense mutations (a change in one DNA base pair that results in the substitution of one amino acid for another in the protein made by the gene) in the gene leucine-rich repeat kinase 2 (LRRK2) are the greatest known genetic contributor to PD and are linked to the incidence of both familial and sporadic forms of the disease. These mutations lead to a hyperactive form of the protein kinase that promotes neurotoxicity. Over time, increases in LRRK2 kinase activity lead to a reduction in the activity of dopamine in the brain, which manifests in the muscle rigidity and tremors that are hallmark symptoms of PD. Over the past several years, drug companies have developed LRRK2 kinase inhibitors that target the adenosine triphosphate (ATP) binding pocket—essentially, the energy store—in the biological system of LRRK2, which is required for LRRK2 signaling.
Vitamin B12 is naturally present in some foods and is also available as a dietary supplement and as a prescription medication. Vitamin B12 deficiency in humans is known to contribute to a variety of neurological conditions and low vitamin B12 levels have been described in patients with idiopathic PD. A recent study showed that low levels of vitamin B12 predict worse motor symptoms for patients early on in PD progression.
“We were surprised to uncover that the chemical compound of vitamin B12 called 5’-deoxyadenosylcobalamin (AdoCbl), which naturally occurs in the body, is a legitimate inhibitor of LRRK2. We studied it in various cellular and animal models of Parkinson’s disease and found it had beneficial effect both in vitro and in vivo,” says Zhenyu Yue, PhD, Professor of Neurology and Neuroscience at the Icahn School of Medicine at Mount Sinai and senior author of the paper. “Our studies provide a starting point that may help us to understand the mechanism underlying the connection between vitamin B12 deficiency and Parkinson’s, hopefully helping to inform the development of new therapeutic agents.”
Specifically, the study team performed a blind, high-throughput screen of 2,000 chemical compounds from a library of FDA-approved drugs to identify which ones had the ability to tamp down the LRRK2 kinase protein in the setting of a test tube. Vitamin B12 proved to be one of very few compounds that both had that ability and are known to be nontoxic. Unlike other compounds being studied in other labs, and in some cases being developed by pharmaceutical companies, vitamin B12 interacts with LRRK2 outside the ATP binding pocket, causing changes of LRRK2 folding or self-assembly.
The team first studied LRRK2 in cultured cells and brain tissue and found that AdoCbl inhibited LRRK2 in the low micromolar range. They then genetically modified fruit flies and C. elegans worms—organisms that show neurological symptoms roughly analogous to human PD—to express the LRRK2 mutation and found that feeding them AdoCbl slowed the decline in dopamine activity in their brains, demonstrating that treatment with AdoCbl was able to reduce these deficits in a dose-dependent manner. Furthermore, they found that AdoCbl corrected abnormal dopamine transmission in cultured tissues from mouse models with the LRRK2 mutation.
“Although more work and better animal models will be needed to unravel the complex biochemistry and molecular pathways of Parkinson’s disease, outside the lab it should be possible to set up human studies right now to see whether boosting vitamin B12 intake could slow the progression of PD,” says Dr. Yue. “Vitamin B12 is very safe and I know clinicians are interested, so why not see if it may have a benefit on patients? For people with this specific genetic mutation, I would say there is hope that we’ll have a treatment in the near future.”
Adam Schaffner, PhD a former student trained under Drs. Yue and Iban Ubarretxena, PhD (another author on the paper) at Mount Sinai, and Xianting Li, PhD, a senior scientist in the Yue Laboratory at Mount Sinai, are the co-first authors of the publication. Researchers from the Academy of Athens, Rensselaer Polytechnic Institute, Case Western Reserve University, University of York, Thomas Jefferson University, and the University of the Basque Country contributed to this research.
This work was supported by awards from the National Institutes of Health, the Michael J. Fox Foundation, the Welcome Trust, and the Centre for Chronic Diseases and Disorders at the University of York.
About the Mount Sinai Health System
The Mount Sinai Health System is New York City's largest integrated delivery system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai's vision is to produce the safest care, the highest quality, the highest satisfaction, the best access and the best value of any health system in the nation. The Health System includes approximately 7,480 primary and specialty care physicians; 11 joint-venture ambulatory surgery centers; more than 410 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report's "Best Medical Schools", aligned with a U.S. News & World Report's "Honor Roll" Hospital, No. 12 in the nation for National Institutes of Health funding, and among the top 10 most innovative research institutions as ranked by the journal Nature in its Nature Innovation Index. This reflects a special level of excellence in education, clinical practice, and research. The Mount Sinai Hospital is ranked No. 18 on U.S. News & World Report's "Honor Roll" of top U.S. hospitals; it is one of the nation's top 20 hospitals in Cardiology/Heart Surgery, Gastroenterology/GI Surgery, Geriatrics, Nephrology, and Neurology/Neurosurgery, and in the top 50 in six other specialties in the 2018-2019 "Best Hospitals" issue. Mount Sinai's Kravis Children's Hospital also is ranked nationally in five out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 11th nationally for Ophthalmology and 44th for Ear, Nose, and Throat. Mount Sinai Beth Israel, Mount Sinai St. Luke's, Mount Sinai West, and South Nassau Communities Hospital are ranked regionally.