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The depth and breadth of the Mass General effort is extraordinary – from cell-based research into disease causation, to the assessment of those cell-based changes in transgenic animal models, to clinical trials involving human patients. A particular strength of the programs at Massachusetts General Hospital is that many of the scientific investigators are physicians and therefore participate in the clinical assessment and treatment of patients with Parkinson’s disease.
Although most cases of PD do not appear to be directly caused by genetic mutations, there are rare examples of families in which the disease runs quite strongly, and can be traced to a specific genetic abnormality. Individuals in whom the symptoms begin before the age of 40 are especially likely to have a strong genetic component. To date, mutations in a total of 7 different genes have been directly implicated in the cause of PD, which has greatly facilitated new discoveries. MIND researchers are actively investigating how these mutations cause parkinsonism, and how the degeneration they produce can be prevented.
Environmental exposures also seem to play a role in PD. MIND researcher Michael Schwarzschild, MD, PhD has a longstanding collaboration with the neuro-epidemiology group at the Harvard School of Public Health, to translate new environmental clues about PD into novel therapeutic targets for slowing the disease. By carefully examining large populations over decades and looking for common diet, lifestyle and environmental exposures among those individuals who develop PD, they have found intriguing clues that point investigators in new directions. Dr. Michael Schwarzschild lab’s research on caffeine, estrogen and their interaction in reducing the risk of PD serves as a prime example of the value of this inter-disciplinary, cross-institutional research team. This collaboration has also substantiated a link between blood levels of urate and a reduced risk of developing PD later in life, an exciting breakthrough that holds great promise for drug discovery.
The Parkinson’s team at MIND is pioneering research that is unraveling the disease mechanisms of Parkinson’s disease and setting the stage for the identification of therapies that can prevent or slow the progress of the disease.
Anne Young, MD, PhD is a world-renowned expert in Parkinson’s disease and other movement disorders. She and her late husband (John B. Penney, Jr.) established the most widely cited model of dysfunctional brain circuitry in Parkinson’s disease. The model has provided the springboard for testing novel interventions in Parkinson’s disease and related disorders including the use of electronic deep brain stimulation. Dr. Young is the Principal Investigator of the MGH/MIT Morris Udall Center of Excellence in PD Research, which brings together scientists in several laboratories at MIND and MIT to try to understand the causes of and molecular events that contribute to Parkinson disease.
Alpha-synuclein MIND was one of the first research institutes in the world to investigate the structure, role, and dysfunction of the protein alpha-synuclein, which accumulates in the brains of both inherited and sporadic cases of PD, as well as other Parkinson-like disorders. This effort has yielded important evidence to suggest that modifying alpha-synuclein could prevent or slow the progression of PD.
Bradley Hyman, MD, PhD has assembled a group of researchers led by Pamela McLean, PhD, that uses sophisticated optical imaging methods and gene transfer techniques to understand why alpha-synuclein becomes toxic to brain cells. This imaging shows that modifications to one end of the protein can result in misfolding and aggregation. The group has found several kinds of molecules which can change the metabolism and effects of synuclein, and therefore reduce this misfolding and toxicity. Alpha synuclein, therefore, is a logical target for preventative or neuroprotective treatments and is a central component of MIND’s drug discovery efforts in PD.
Dr. Young’s laboratory is also examining the biology of alpha-synuclein in a group of Parkinson-like disorders, the Multiple Systems Atrophies. These studies suggest novel mechanisms in synuclein turnover, which may be relevant for treatments targeted at this protein.
Dr. Schwarzschild and his laboratory are focused on understanding molecular pathways contributing to Parkinson’s disease. His laboratory’s work on caffeine, and the brain signals it targets, has recently converged with major human studies to suggest that caffeine and related drugs may help protect the brain cells lost in Parkinson’s disease. Adenosine A2A receptors, which are part of the brain’s circuitry that control movement are very sensitive to caffeine. Research suggests that drugs that block these receptors can partially reverse motor deficits in PD. A2A receptors may also be manipulated to reduce dyskinesia -- the excessive movements that can be a disabling side effect of long-term treatment with L-dopa, the mainstay therapy for PD.
Dr. Schwarzschild’s research group has also examined the potential interactions between A2A receptors and estrogen, because PD is less common in women and epidemiological studies have shown that caffeine is linked to a reduced risk of PD only in those women who have not taken post-menopausal estrogen replacement therapy. Current experiments use genetically engineered mice to understand these findings and to examine their implications for drug discovery.
Most recently, an exciting breakthrough catalyzed by collaboration with the Harvard School of Public Health is related to the role of urate, a powerful antioxidant molecule, in PD. Higher levels of urate in the general population are associated with a reduced risk of developing Parkinson’s disease. And amongst those who have already developed the disease, higher urate levels are a predictor of a more favorable rate of disease progression.
The role of blood levels of urate discovered by Dr. Schwarzschild’s lab has broad implications for drug discovery – and a clinical trial for the use of urate as a protective drug for PD will be launched in late 2008. Dr. Schwarzschild is also working to understand the mechanisms behind this protective effect in the laboratory, by conducting studies in several different mouse models of Parkinson’s disease to determine how urate may prevent brain cell degeneration.
Dr. Young’s laboratory has focused on the role of abnormal gene expression in PD, the tightly regulated process of turning genes on and off in brain cells. This group, headed by Ippolita Cantuti-Castelvetri, PhD is examining both mouse brains and post-mortem human brain samples with advanced tools such as Laser Capture Microdissection, to isolate sick brain cells, and gene array techniques that record the status of thousands of genes in these sick cells. They have found that specific sets of genes are abnormally changed in the PD brain. An additional intriguing finding is that this group of genes is different in male brains than in female’s brains, providing new biological clues to the gender differences already observed in PD incidence.
Because MIND scientists studying Parkinson’s are also physicians, and MGH has one of the world’s strongest clinical programs in PD, investigators are focused on finding the critical links between scientific discoveries and their implications for treatment.
To speed the pace of drug discovery, MIND established the Parkinson’s Disease Therapy Initiative to translate laboratory advances into new therapies. Several projects are underway to take maximum advantage of the innovative investigative techniques that are unique to MIND’s laboratories.
MIND’s seminal work on the protein alpha synuclein opens the door to seeking drugs that would reduce its toxicity. We have developed unique and powerful ways to test for the presence of dangerous forms of alpha-synuclein and to measure individual brain cells’ ability to neutralize its deadly effects. Our drug discovery laboratory, headed by Dr. Alex Kazantsev, is working closely with Dr. Hyman’s group to seek drug-like molecules that can clear toxic protein from brain cells, as well as neuroprotective factors that can bolster the body’s own defenses against misfolding. This drug discovery work has been dramatically successful, identifying several compounds that are targets for further testing in animal models of the disease.
Dr. Schwarzschild’s laboratory as identified blood urate levels as the first molecule to be directly tied to the progression of typical PD. Urate and its metabolic pathway are particularly amenable to new and existing drug treatments and dietary factors. This discovery provides a substantial new opportunity to understand and possibly slow the neurodegeneration that underlies the progressive decline of PD patients, and work is proceeding quickly to actualize this goal. A clinical study to see whether manipulating urate levels with new or existing drugs could slow disease progression is currently being planned to launch in late 2008, with funding from the Michael J. Fox Foundation.
Dr. Schwarzschild’sgroup has shown that caffeine, as well as more specific blockers of the A2A receptor, can protect the dopamine-containing brain cells that are progressively lost in PD. Additionally, by combining their respective expertise on adenosine and glutamate signaling pathways in the brain, Dr. Schwarzschild’s and Dr. Young’s laboratories recently identified a dramatic synergistic effect: by blocking adenosine A2A and glutamate (mGlu5) receptors in combination, the individual anti-parkinsonian effects on movement were markedly enhanced. The potential symptomatic benefits of adenosine A2A blockers could be leveraged into even more dramatic improvements for PD patients through this basic research teamwork at MIND.
The clinical activities at MGH are organized around the Partners Parkinson Disease and Movement Disorder Center. Directed by Dr. John Growdon, the Center evaluates more than 700 new and 2,000 returning patients per year and several MIND physician-scientists care for PD patients in the Center. This Center and MIND investigators are also active members of the Parkinson’s Study Group, a non-profit, cooperative group of Parkinson's disease experts from medical centers in the United States and Canada which coordinates drug clinical trials under the principles of open scientific communication, peer review, and full disclosure of potential conflicts of interest. Numerous clinical trials of new medical treatments for Parkinson's Disease have been conducted at MGH, many of which are now available to patients.
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