Discovery may lead to a treatment to slow Parkinson's disease
Researchers have found that an interaction between a mutant gene and alpha synuclein in neurons leads to hallmark pathologies seen in Parkinson’s disease, findings that may lead to new mechanisms and targets for neuroprotection.
Laura A. Volpicelli-DaleyUsing a robust model for Parkinson’s disease, University of Alabama at Birmingham researchers and colleagues have discovered an interaction in neurons that contributes to Parkinson’s disease, and they have shown that drugs now under development may block the process.
The research team has shown that the most common genetic cause of Parkinson’s disease — a mutant LRRK2 kinase enzyme — contributes to the formation of inclusions in neurons, resembling one of the hallmark pathologies seen in Parkinson’s disease. These inclusions are made up of aggregated alpha synuclein protein, which — the research also shows — can be prevented from forming by using two LRRK2 kinase inhibitor drugs now being developed for clinical use.
The interaction between mutant LRRK2 kinase and alpha-synuclein “may uncover new mechanisms and targets for neuroprotection,” the researchers write in a recent Journal of Neuroscience paper. “These results demonstrate that alpha-synuclein inclusion formation in neurons can be blocked and that novel therapeutic compounds targeting this process by inhibiting LRRK2 kinase activity may slow progression of Parkinson’s disease-associated pathology.”
The potential clinical applications for novel neuroprotection strategies in LRRK2-linked Parkinson’s need to be tested in other preclinical models of Parkinson’s disease, say the researchers, led by corresponding author Laura A. Volpicelli-Daley, Ph.D., and senior author Andrew B. West, Ph.D., Center for Neurodegeneration and Experimental Therapeutics, UAB Department of Neurology.
“These data give us hope for the clinical potential of LRRK2 kinase inhibitors as effective therapies for Parkinson’s disease,” Volpicelli-Daley said. “The LRRK2 kinase inhibitors may inhibit the spread of pathologic alpha-synuclein, not only in patients with LRRK2 mutations, but in all Parkinson’s disease patients. Future studies to validate the safety and efficacy of the LRRK2 inhibitors will be necessary before testing the inhibitors in human clinical trials.”
Besides Parkinson’s disease, alpha-synuclein also plays a central role in development of dementia with Lewy bodies and multiple system atrophy, and it is associated with Alzheimer’s disease and other neurodegenerative disorders.
Primary hippocampal neurons from mice expressing G2019S-LRRK2. The neurons were treated with alpha-synuclein fibrils, and 18 days later immunofluorescence was performed. The magenta shows phospho-alpha-synuclein inclusions in the cell bodies and throughout the axons, which are visualized as green.Research detailsThe Parkinson’s disease model developed by Volpicelli-Daley applies very low concentrations of pre-formed fibrils of alpha-synuclein to in vitro or in vivo neurons. This causes formation of modified alpha-synuclein inclusions that share morphology with those found in the Parkinson’s disease brain after death.
They used this model to test the effects of neuron expression of the mutant LRRK2 (“lark two”) kinase, G2019S-LRRK2, on the formation of the inclusion pathology.
They found that:
- G2019S-LRRK2 enhanced alpha-synuclein inclusions in primary hippocampal neurons from the hippocampus region of the brain, 18 days after fibril exposure, as compared with neurons that over-expressed normal LRRK2.
- The effects of G2019S-LRRK2 expression in the fibril-exposed neurons were lessened by very low concentrations of potent and selective preclinical drugs that inhibit LRRK2 kinase. This suggested that the kinase activity of G2019S-LRRK2, which adds a phosphate onto target proteins, underlies the faster formation of pathologic alpha-synuclein inclusions.
- G2019S-LRRK2 expression enhanced alpha-synuclein inclusion formation in dopamine neurons from the region of the brain called the substantia nigra pars compacta. The substantia nigra pars compacta is the area of the brain that dies in Parkinson’s disease, so this experiment further supports a link between the G2019S-LRRK2 mutation and Parkinson’s pathogenesis.
Andrew B. WestIn fluorescence-recovery-after-photobleaching experiments, they found there was a larger pool of mobile alpha-synuclein, as opposed to membrane-bound alpha-synuclein, in neurons that expressed G2019S-LRRK2. Recent work by others has shown that mobile alpha-synuclein is prone to misfolding and aggregation, so the researchers hypothesize that the G2019S-LRRK2 mutation may contribute to Parkinson’s susceptibility by boosting the amounts of mobile alpha-synuclein in neurons.
Besides Volpicelli-Daley and West, co-authors of the paper “G2019S-LRRK2 expression augments alpha-synuclein sequestration into inclusions in neurons” are Hisham Abdelmotilib, Zhiyong Liu, Lindsay Stoyka, João Paulo Lima Daher and Kyle Fraser, all of the Center for Neurodegeneration and Experimental Therapeutics, UAB Department of Neurology; Austen J. Milnerwood, Centre for Applied Neurogenetics, University of British Columbia; Vivek K. Unni, Jungers Center for Neurosciences Research and Parkinson Center of Oregon, Oregon Health & Science University; Warren D. Hirst, Pfizer Neuroscience and Pain Research Unit, Cambridge, Massachusetts; Zhenyu Yue, Departments of Neurology and Neuroscience, Icahn School of Medicine at Mount Sinai; Hien T. Zhao, Ionis Pharmaceuticals, Carlsbad, California; and Richard E. Kennedy, Comprehensive Center for Healthy Aging and Division of Gerontology, Geriatrics, and Palliative Care, UAB Department of Medicine.
Grants to fund this work came from the American Parkinson’s Disease Association, the Michael J. Fox Foundation LEAPS Award and the National Institutes of Health NS064934.
Volpicelli-Daley is an assistant professor in the Department of Neurology.
West is co-director of the Center for Neurodegeneration and Experimental Therapeutics, and the John A. and Ruth R. Jurenko Professor of Neurology at UAB.
NEURAL Conference draws new minds to Neuroscience
NEURAL, the cornerstone effort of the UAB Neuroscience Roadmap Scholars Program, is moving to change this reality. NEURAL, which stands for “National Enhancement of Underrepresented Academic Leaders,” is an annual conference targeted toward trainees and graduate students in the neuroscience fields who are members of underrepresented groups. Bringing together students and trainees from inside and outside UAB, the NEURAL 2016 conference offers opportunities to present original research, and to interface with respected neuroscientists from across the country.
The Neuroscience Roadmap Scholar program and its flagship NEURAL conference were conceptualized by Farah Lubin, PhD, and Lori McMahon, PhD, who received funding on an R25 NIH grant in order to launch the program. Although the undergraduate programs which interacted with neuroscience at UAB included a diverse population of students, Lubin and McMahon realized that racial and ethnic minorities and those with physical or mental disabilities were still underrepresented at the graduate level. The UAB Neuroscience Roadmap Scholar program was created as a means to provide both incentive and support for graduate students who are racial or ethnic minorities, and/or who have a physical or mental impairment from a broad range of scientific fields, including chemistry, biology, and bioengineering, to pursue careers in neuroscience. The UAB Neuroscience Roadmap Scholar program is hugely supported by the Neuroscience community and faculty who serve as career coaches for the scholars.
The UAB Neuroscience Roadmap Scholar program held its NEURAL 2016 conference June 22-24 on UAB’s campus with opening ceremonies at the Birmingham Civil Rights Institute. Bringing together roughly 75 UAB students and 50 students from outside UAB, it offered not only insight into neuroscience career paths, but also professional development workshops on personal finance, electronic portfolios, successful paper submissions, and dealing with stereotype threat.
One of the tremendous offerings of the NEURAL conference is its ability to bring in renowned neuroscientists who offer unique perspectives. At the NEURAL conference in 2015, Roger Nicoll, MD, a professor at UCSF’s School of Medicine and recipient of the Gruber Prize in Neuroscience, discussed his struggles with severe dyslexia.
The NEURAL 2016 conference featured Gordon E. Legge, PhD, a professor of psychology from the University of Minnesota who heads the Minnesota Laboratory for Low-Vision Research. Author of more than 400 papers, and the recipient of a wide range of professional honors, including the Charles F. Prentice Medal from the American Academy of Optometry and the Access Achievement Award from the University of Minnesota, Legge himself is visually impaired.
Students and trainees, who participated in a faculty-judged poster session during the conference, were given the opportunity not only to hear from Legge and other distinguished speakers, but to interact with them one-on-one. Yisel Cantres Rosario, PhD, of the University of Puerto Rico Medical School, was one of the trainee participants. In a letter following the conference, she articulated the importance of the opportunities offered by the NEURAL conference. “I would have liked to participate in a small meeting like this when I was a graduate student,” she wrote. “I have participated in a good number of big meetings, but because of the amount of people attending those conferences, we dilute ourselves and are not able to interact with everybody as we did in NEURAL. I personally talked to all the keynote speakers opening new doors of communication, which is a critical component of my career, now that I am beginning as a post-doctoral. I came to Puerto Rico with a lot of ideas for my research and also to help graduate students from our institution, thanks to you. Congratulations to all for such a good meeting for underrepresented students! It means a lot for us and shows how much you care for your students.”
Lubin says that the gears are already turning in preparation for the conference’s third year. Thanks to institutional support, she sees the Neuroscience Roadmap Scholar program and the NEURAL conference flourishing well into the future and serving its critical mission to draw underrepresented graduate students and trainees into neuroscience. “You can’t model what you haven’t seen,” she says. “The more examples we put in front of students, the more we make it clear they have no excuse to not succeed.”
Research Grant Proposals
Research Grants for Emerging Scholars
Request for Proposals
Proposal Deadline: Friday, September 2, 2016, at Noon
Grant Start Date: October 1, 2016
Eligible Applicants: Graduate students, postdoctoral trainees, non-tenure earning instructors, and non-tenure earning faculty
Award Level: $25,000 for one year
Contact and Submit to: Vicki Hixon email@example.com
The Civitan International Research Center is requesting proposals for clinical or basic science research aimed at enhancing our current understanding of typical and atypical brain development, autism spectrum disorders, Down and Rett syndromes, developmental disabilities, impaired cognitive development, and the effects of environmental toxins on the development of the brain. The $25,000 award may be used as a stipend supplement or for direct projects costs.
Proposals should consist of a single PDF document containing a two page description of the planned research; a letter of endorsement from the mentor; and CV from the applicant.
The mission of the CIRC is to improve the well-being and the quality of life of individuals and families affected by neurodevelopmental disabilities; to provide interdisciplinary clinical and research training in neurodevelopmental disabilities; to utilize this knowledge to develop and provide high quality exemplary services and programs; and to exchange information in a timely way with consumers, practitioners, scientists, and society.