2. National Parkinson Foundation is using its distribution to fund the following:

Project Title:  NPF Quality Improvement Research Initiative

Investigator(s):

Jay Nutt, MD, Medical Director, NPF Center of Excellence at Oregon Health Sciences University.

Andrew Siderowf, MD, MSCE, Fellow at the University of Pennsylvania Institute on Aging and Medical Director of the University of Pennsylvania Parkinson’s Disease and Movement Disorders NPF Center of Excellence.

Project Description:  NPF, in partnership with 43 top medical centers (NPF's Centers of Excellence), has launched the first data-driven quality improvement research initiative to systematically improve care for every patient diagnosed with Parkinson’s disease. With a goal of tracking every patient seen in every NPF Center of Excellence (35,000-50,000 patients worldwide), this research initiative will generate the largest outcomes database in Parkinson’s disease.  Our ultimate aim is to create and share models of excellent care, so that every Parkinson’s patient receives the most effective treatment options available, whether they are seen by a specialist at a NPF Center of Excellence, a general neurologist or their primary care physician.  Financial support from the Unity Walk will support the initial pilot test of NPF's Quality Improvement Research Initiative, which involves collection and analysis of 600 patient records to be completed by January 2010.

3. Parkinson's Action Network (PAN), founded in 1991, is the unified education and advocacy voice of the Parkinson's community, fighting for a cure. Through education and interaction with the Parkinson's community, scientists, lawmakers, opinion leaders, and the public at large, PAN works to increase awareness about Parkinson's disease and advocates for increased federal support for Parkinson's research.

PAN also provides the information and resources necessary to empower people with Parkinson's disease to act on their own behalf and gain a greater sense of control over their health and their future. For more information on PAN, please see its website at www.parkinsonsaction.org.

4. Parkinson’s Disease Foundation is using its distribution to fund the following:

Project Title: Mechanism of FADD recruitment and activation in mutant LRRK2-induced neurodegeneration

Investigator: Hardy Rideout, Ph.D.

Project Description:  The most common genetic mutations leading to PD occur in a gene called LRRK2.  The LRRK2 gene is responsible for a protein that plays a role in signaling cells to die.  We have shown that, in neuron cells cultured in the laboratory, the LRRK2 protein must form a complex with another protein, called FADD, in order to induce cell death.  We also know that LRRK2 proteins commonly link together in two-molecule chains, and longer chains are formed when LRRK2 is mutated.  We propose that the formation of chains longer than two proteins is a critical step in the molecular pathway to cell death.  Our project aims to determine how long the chains must be for them to associate more frequently with FADD, and to discover whether this association can be blocked.  We also will examine brain tissue from people whose PD was due to LRRK2 mutations in order to better understand the connection between LRRK2 and FADD.

Project Title: The contribution of dopaminergic system in pathological gambling in Parkinson’s disease

Investigator: Antonio Strafella, M.D., Ph.D.

Project Description:  The motor symptoms of Parkinson’s disease result from a loss of the chemical messenger dopamine in certain areas of the brain.  Drug therapies to relieve motor symptoms generally work by increasing dopamine levels, but these therapies can have side effects.  In the last five years, researchers and physicians have become more aware of people with Parkinson’s developing impulse control disorders, including compulsive gambling, after beginning dopaminergic medication.  This may happen because dopamine is involved not only in how the brain controls movement, but also in its reward system.  This study uses brain scans with positron emission tomography (PET) of people with PD to characterize abnormalities in dopamine levels in two brain areas, the striatum and the prefrontal cortex, comparing people who have developed pathological gambling with those who have not.  Newly available PET tracers used to assess dopamine levels make it possible to assess dopaminergic dysfunction more accurately and comprehensively than ever before.

5. The Michael J. Fox Foundation for Parkinson's Research is using its distribution to fund the following:

PD Online Research  is an efficient Web-based platform for research professionals across the globe to engage daily on key research hurdles and breaking scientific findings.  This virtual workplace has a simple goal:  enable quicker knowledge turns and therefore faster progress toward transformative therapies.

6. The Parkinson Alliance is using its distribution to fund the following:

Project Title: Creating dopaminergic neurons with authentic Parkinson's disease - A new path to drug discovery and understanding mechanisms of neurodegeneration

Investigator: Dr. J. William Langston, Founder, CEO, and Scientific Director of the Parkinson's Institute.

Objective: The goal of this study is to derive induced stem cell lines (known as human-induced pluripotent stem cells or hiPSCs) from skin biopsies or hair taken from adult patients with Parkinson's disease (PD).  More specifically, we wish to derive hiPSCs from patients with parkinsonism due to genetic causes, including the LRRK 2 G2019S and alpha-synuclein triplication mutations. We will then use established technologies to differentiate these cells into dopamine neurons, one of the main neuronal populations that degenerate in PD.  This work will also include collaborations with academic medical centers as well as industry.

Hypothesis to be tested:  The underlying hypothesis of this proposal is that these "re-born" dopaminergic neurons that started out as skin or hair cells from adult patients with PD will recapitulate one or more of key molecular aspects of neural degeneration associated with PD in a tissue culture dish (“PD in a dish”).  We believe that this is likely since these cells will have been obtained from patients with parkinsonism of a known cause and that cause will have been carried with the hiPSCs in the form a known mutation in their DNA. 

Significance: These proposed studies have the potential to provide an entirely new tool for investigating disease mechanisms of PD.   Furthermore, these "parkinsonian cells" could provide a transformative way to screen large number of drugs to see if they can prevent or even reverse the disease process.  The power of this approach is that it could, for the first time, provide authentic Parkinson's disease cells that are not a "best guess" model, but neuronal populations with authentic disease.  This is important because the results would be directly relevant to humans with the disease.  It is worth noting that we already have a large number of potentially “neuroprotective” drugs ready for screening. 

Deliverables/Milestones:  The specific milestones for this project, which we estimate will take one year to 18 months, are as follows:

1.  Obtain appropriate human subjects approvals, including IRB approval for skin biopsies, and SCRO approval for derivation of iPS cells.
2.  Recruitment of 15 PD patients and controls for biopsy and establishment of fibroblast cultures.
3.  Reprogramming of fibroblasts for induced pluripotent cells (iPSCs).
4.  Characterization of ~150 iPSC clones for pluripotency and karyotype.
5.  Directed differentiation of iPSCs into dopaminergic neurons.

While this is a very ambitious set of deliverables, but we believe that they are achievable within the timeframe proposed for this research project.

Project Title:  Novel, small-molecule inhibitors of  a-synuclein assembly and toxicity for disease-modifying therapy of Parkinson's disease.

Investigator:  Dr. Gal Bitan

Project Description:  The generous gift of The Parkinson Alliance and Team Parkinson will support exciting research in the Bitan Laboratory geared towards development of disease-modifying therapy for Parkinson's disease (PD). Current treatment of PD focuses on compensation for dopamine deficiency, predominantly by using L-dopa. Though this kind of treatment is successful in alleviating major symptoms, such as tremor, it does not address “non-dopaminergic” symptoms, including falling and freezing, which affect 80-90% of patients with PD and 100% of patients with early-onset PD, or dementia which afflicts ~30% of patients with PD. These non-dopaminergic symptoms are major causes of mortality and morbidity in PD. In addition, treatment with L-dopa causes complications such as “off-time” and dyskinesia (involuntary movement). To address these unmet needs, disease-modifying, rather than symptomatic, therapy is needed. We have discovered a new experimental drug that disarms what most researchers believe to be real culprit causing PD - toxic aggregates of a protein called alpha-synuclein. These toxic aggregates are the main component of Lewy bodies, the hallmark pathologic lesion in the brain of patients with PD. The new drug inhibits the formation of these toxic aggregates and thereby prevents the initial processes that lead to development of PD. Through collaboration with Dr. Bronstein's group, the new drug was found to block the toxic effect of alpha-synuclein aggregates in cultured cells and zebra fish. The fish, which without the drug are severely deformed and die within a few days, appear healthy and normal by simple addition of the drug to the water in which they swim. Related experiments in mice show that the drug can get into the brain and remove toxic protein aggregates.

With the help of The Parkinson Alliance and Team Parkinson, we will develop this promising research in pre-clinical studies in transgenic mice in collaboration with Dr. Chesselet. Specifically, we will use mice engineered to overexpress human alpha-synuclein. The mice develop alpha-synuclein aggregates in the brain and show motor deficits already at 2 months of age. We will conduct experiments to optimize dose and treatment duration examining the effect of the drug on clearance of alpha-synuclein aggregates in the brain and on the motor abilities of the mice. In addition, we will conduct pharmacological studies to determine the optimal route of administration of the drug. We expect that these pre-clinical experiments will lead to FDA approval of Investigational New Drug (IND) status for our lead compound, facilitate initiation of clinical trials, and hopefully result in effective treatment and cure for PD.

Project Title:  Is there abnormal network activity in the motor cortex of 6-OHDA lesioned mice.

Investigator:  Dr. Carlos Portera, M.D., PhD

Project Description:  The current treatments for Parkinson disease (PD) offer some symptomatic relief, but often at the cost of serious side effects, including dyskinesias. The introduction of deep brain stimulation (DBS) in the treatment of PD two decades ago has arguably been the most effective treatment strategy since the discovery of levodopa. Understanding the exact mechanisms of how DBS helps PD patients will help improve this therapeutic strategy. A recent study using the 6-hydroxydopamine (6-OHDA) rodent model of PD (Gradinaru et al., 2009) suggests that DBS may help by reducing the activity of the subthalamic nucleus (STN) through its effects on the firing of neurons in motor cortex, which is the part of the brain that controls movement. This raises the possibility that neurons in the motor cortex of PD patients fire less than normal, leading to an overactive STN that produces some of the symptoms of PD. I propose to test the hypothesis that neurons are hypoactive in the motor cortex of mice that had been rendered parkinsonian by injection of the neurotoxin 6-OHDA into the substantia nigra. Specifically, I intend to examine the spontaneous activity of neurons in the motor cortex of mice before and after administering 6-OHDA. We will use the cutting-edge technique of two-photon calcium imaging to record the activity of large numbers of cortical neurons non-invasively.

These experiments will shed light into the mechanisms of circuit dysfunction in PD and may lead to improved treatments for this devastating disorder.

7. The Parkinson’s Institute and Clinical Center is using its distribution to fund the following:

Project Title:  Epidemiologic Studies of PD Etiology

Investigator:  Tanner CM, Goldman SM, Langston JW

Objective:  The goal of this study is to further investigate the hypothesis that Parkinson’s disease is a complex disorder with both genetic and environmental determinants

Background:  The cause of Parkinson’s disease is not known.  Our work indicates that no single factor causes Parkinson’s disease.  Instead, combinations of risk factors and genetic makeup determine whether an individual develops Parkinson’s disease or not. Our recent work found that specific environmental factors only increase Parkinson’s disease risk in those carrying certain genetic variants.  This effect was very large for some factors, with up to an 11-fold increased risk of Parkinson’s disease.  The goal of this research project is to expand on this ongoing work, focusing on the interplay between inherited (genetic) and acquired (environmental) factors to identify the causes of Parkinson’s disease.

Methods/Design:  We will conduct secondary analyses on the combined effects of genes and environment, taking advantage of extensive work in several large epidemiologic studies. We will focus our work in three study populations of nearly 2000 individuals.  Subjects have been identified by movement disorders experts across the U.S. and Canada.  One population is comprised of over 200 pairs of twins where one twin has Parkinson’s and one doesn’t.  Detailed lifelong information on environmental risk factors and DNA has been collected. DNA has been tested for over 1500 variations in 120 genes thought to play a role in Parkinson’s disease. We will take advantage of these populations to investigate the following hypotheses: 1) The risk of Parkinson’s disease is higher with exposure to occupational chemicals and specific pesticides, and 2) In individuals with variants of genes encoding proteins involved in the metabolism of these compounds, the effect of these exposures will be increased or decreased, in accordance with the metabolic effect of the specific variant.

Relevance to Parkinson’s disease:  Interplay between genetic and environmental risk factors has long been proposed as the cause of most Parkinson’s disease, however very few studies have ever investigated this in any detail.  This project will take advantage of a rich resource of environmental and genetic information in very large study populations.  The existing data in these populations provides the opportunity to investigate these complex effects on the cause of Parkinson’s disease, focusing on common exposures that could be easily translated into a preventive intervention.