The 2007 Parkinson's Unity Walk Funds Research Grants

Through the generous support of its corporate sponsors, 100% of all donations made to the Parkinson's Unity Walk are distributed among the major U.S. Parkinson's disease foundations for Parkinson's disease research. The foundations include: (1) American Parkinson Disease Association; (2) the National Parkinson's Foundation; (3) the Parkinson's Action Network; (4) the Parkinson's Disease Foundation; (5) the Michael J. Fox Foundation for Parkinson's Research; (6) The Parkinson Alliance; and (7) the Parkinson's Institute.

We are excited to share with you information about the following grants —all of which are made possible from 2007 Parkinson's Unity Walk distributions. We will update the grants with progress reports as they are made available to us.


1. The American Parkinson Disease Association is using its distribution to fund:

Grant awarded to: Matthew LaVoie, MD
Project Title: Dissecting the Anti-Apoptotic Function of Parkin and the Impact of PD-Linked parkin Mutations

Project Description: Autosomal-recessive mutations within Parkin are associated with a common form of familial Parkinson’s disease (PD) and spontaneous apoptosis and/or mitochondrial abnormalities in multiple animal models. Parkin-deficiency in humans causes a progressive loss of neurons within the ventral midbrain, indicating that parkin’s function must be particularly critical to the survival of these cells. Given the long-standing interest in mitochondrial dysfunction in PD, the evidence of a mitochondrial function for parkin, and the crucial role mitochondria play in the regulation of apoptosis, we hypothesize that 1) parkin increases the threshold for mitochondrial cytochrome c release and 2) that known pathogenic PD-linked parkin mutations will not support this function. Our preliminary data support a direct influence of parkin on mitochondria. Our hope is that insight into the pro-survival function of parkin may lead to novel therapeutic strategies or a deeper understanding of the factors responsible for idiopathic PD.

Grant awarded to: Ming Guo, MD, PhD
Project Title: Characterization of the Function of a Pink1 Binding Protein

Project Description: Mutations in pink1 gene cause familial Parkinson's disease (PD). Pink1 encodes a serine-threonine kinase that is localized to mitochondria. We have recently shown that pink1 acts upstream of parkin to regulate mitochondrial morphology and function in Drosophila. Identifying pink1 interacting factors and investigating how pink1 and these
factors function may provide mechanistic understanding of PD pathogenesis. Here, we provide preliminary data on identifying a pink1 binding partner, sib. The proposal details studies of the in vivo function of sib using Drosophila as a model system. We will examine phenotypes of both loss of sib function and sib overexpression to determine if there are any mitochondrial defects, as well as dopaminergic neuronal loss, associated with altered sib function. We will also initiate studies to determine if pink1 and sib function in the same genetic pathway.

Grant Awarded to: Stephan Witt, PhD
Project Title: Determining Why Phosphorylation of alpha-synuclein at Serine 129 Causes Toxicity

Project Description: The Parkinson’s disease-related protein alpha-synuclein (a-syn) is the focus of this proposed research. We seek to determine why phosphorylation of WT a-syn at serine 129 causes toxicity. We hypothesize that phosphorylation at serine 129 results in a deleterious interaction with some unknown cellular protein. To test this hypothesis, we propose to carry out a two-hybrid screen in which human WT a-syn is screened against a library of yeast genes. This is a classic method to identify protein-protein interactions. In parallel with our analysis of WT a-syn we will screen for binding partners of the S129A mutant; this mutant cannot be phosphorylated at position 129. We expect that this proposed subtractive two-hybrid screen will permit the identification of those proteins that only associate with the phosphorylated form of WT a-syn. Proteins that associate with WT a-syn but not S129A could be potential targets for novel therapeutics.


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

Grant Awarded to: Michael S. Okun, MD - Co-Director Movement Disorders Center, University of Florida
Project Title: The MOST Study: Mood and STN DBS

Project Description: The aim of this study is to characterize the changes in mood seen following deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson disease (PD). Specifically, this study aims to characterize these changes in bilateral versus unilateral DBS patients. Two institutions are participating, The University of Florida Movement Disorders Center (UF) and the Mount Sinai School of Medicine (MS). The UF site aims to enroll 30 unilateral STN DBS subjects while the MS institution will enroll 30 simultaneously implanted bilateral STN DBS subjects. Each subject will receive an identical post-surgical follow-up regimen including mood testing utilizing the: Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Young Mania Rating Scale, and the Yale-Brown Obsessive Compulsive Disorder Scale. These neuropsychological tests are administered together six times following the electrode(s) implantation. The tests are administered at 2-weeks, 4-weeks, 2-months, 4-months, 6-months, and 1-year, respective to the implantation date. At study completion, these data will be analyzed to determine changes between groups and if simultaneous bilateral analyzed to determine changes between groups and if simultaneous bilateral implantation increases the risk of adverse side effects. Additionally we will examine co-morbid criteria which may correlate to the incidence of adverse mood changes following surgery.

The research is prospective and blinded between sites, thus there are no results that can be reported. The UF site has met enrollment criteria of ten patients per year during the first and second year of the study. The Mt. Sinai site has enrolled eight during year two for a total of eleven. Mt. Sinai has a plan for year three to recruit the requisite number of patients for the study.

The research is ongoing, but important for safety and targeting in PD surgery. The research will define the mood and behavioral effects of DBS in STN. There are few studies despite the widespread use of DBS. There are no studies available to patients and practitioners looking at the important use of staging procedures. The knowledge obtained in this study may provide information essential to patient selection, surgical target selection, and improved patient management. Such knowledge is significant as non-motor effects of DBS may have a larger impact than the motor effects when considering quality of life and overall function.


Grant Awarded to: Nutan Sharma, M.D., Ph.D. - Massachusetts General Hospital
Project Title: “TorsinA: Critical for Dopamine Neuron Survival.”

Project Description: Parkinson’s disease (PD) is characterized by the loss of dopamine neurons in the substantia nigra. Apoptosis is thought to play a role in the pathogenesis of PD. Thus, in order to slow or halt the progression of PD, it is essential to understand the factors that affect apoptosis. We have identified the protein, torsinA, as essential to the survival of dopamine neurons in a transgenic mouse model. TorsinA was first identified because a deletion of a glutamic acid residue near the carboxyl terminus results in early-onset generalized dystonia. The function of torsinA is unknown. However we have found, in a transgenic mouse model, that expression of mutant torsinA results in a 60% reduction in dopamine neurons in the substantia nigra. Interestingly, in a transgenic mouse model expressing wild type torsinA we found a 90% increase in dopamine neurons in the substantia nigra. These data indicate that torsinA is crucial for dopamine neuron survival. This is the first evidence indicating that torsinA plays a role in the survival of dopamine neurons. The hypothesis-driven experiments proposed in this application are designed to determine the intracellular role of torsinA in promoting the survival of dopamine neurons.

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:

Grant Awarded to: Jane Driver, MD, MPH - Brigham and Women's Hospital, MA,
Project Title: Non-Steroidal Anti-Inflammatory Drug, Vitamin, and Estrogen Use and the Risk of Parkinson’s Disease in a Prospective Cohort


Project Description: Parkinson’s disease is a common neurodegenerative disease that causes significant disability and hastened death. As a result of our aging population, Parkinson’s disease (PD) will become twice as common over the next generation. There is currently no known prevention for PD, but a number of drugs have been proposed. Inflammation is an important part of the disease process in PD, and there is some evidence that anti-inflammatory drugs like aspirin and ibuprofen may prevent the disease. Compared to men, women are at half the risk of PD, and estrogen seems to protect neurons from developing PD in animal studies. Finally, anti-oxidant vitamins such as vitamins C and E may protect nerve cells from damage. Although these drugs seem promising based on experiments in animals, evidence in humans is sparse and there is as yet no consensus regarding their use. We therefore propose to examine the relationship between nonsteroidal anti-inflammatory drugs, vitamins and estrogen and the development of PD using the Physicians and Women’s Health Studies (PHS and WHS). Both studies were originally prevention trials to determine if aspirin prevents heart disease and certain vitamins prevent cancer. The studies have detailed information on drug and supplement use. Over 22,000 physicians participated in the PHS and nearly 40,000 female health professionals in the WHS. These studies have the large numbers of people required to detect the preventive effect of a drug, and were carefully constructed for this purpose. We will perform statistical analysis to determine if the regular use of anti-inflammatory drugs, vitamins or estrogen decreases the risk of PD in these cohorts.

Grant Awarded to: Taslimarif Saiyed, Ph.D - University of California, San Francisco, CA,
Project Title: Regulation of Vesicular Monoamine Transporter: a potential role in Parkinson disease

Project Description: Parkinson’s disease (PD) involves specific degeneration of dopaminergic-neurons in brain leading to dopamine-deficiency resulting in motor disorders and disability. Dopamine is thought to play a crucial role in the process, although how remains unclear. Transport of neurotransmitters from cytoplasm into synaptic vesicles is required for regulated exocytotic release. Since vesicular monoamine transporter 2 (VMAT2) protects against the exogenous parkinsonian toxin MPTP, it may similarly protect against dopamine toxicity. This proposal will explore the novel hypothesis that another synaptic vesicle protein, synaptobrevin, regulates with VMAT2 function. This will help us to understand how synaptic vesicle filling affects quantal size and to determine whether regulation of VMAT2 by synaptobrevin can influence cytosolic dopamine and hence the vulnerability to degeneration. Preliminary data suggest formation of the SNARE complex involved in exocytosis disinhibits VMAT2, indicating a relationship between neural activity and VMAT2 that may also influence vulnerability. To characterize the inhibition of VMAT2 by synaptobrevin, I will use biochemical techniques to further identify the sites of interaction. I will use this information along with amperometry and synaptobrevin-resistant versions of VMAT2 identified in this proposal, to assess the physiological significance for transmitter release and dopamine clearance from the cytoplasm, where it has recently been shown to injure cells and may thus contribute to PD.

Grant Awarded to: Esther Wong, Ph.D - Albert Einstein College of Medicine, NY
Project Title: Role of different types of ubiquitination in degradation of alpha-synuclein by autophagy

Project Description: a-synuclein is a protein that accumulates inside nerve cells in patients with Parkinson’s disease (PD), contributing to the death of these cells and the beginning of symptoms. This proposal intends to elucidate the mechanisms by which a-synuclein is normally eliminated in a healthy brain and the reasons why this removal does not happen in PD patients. All cells are endowed with a variety of surveillance systems (autophagy for example) that detect unwanted or abnormal proteins and eliminate them before they become toxic to the cells. However, it is not clear how the cells decide which surveillance system to use for the elimination of a given protein. We hypothesize that the cells may use different “tagging” patterns (different types of ubiquitination) to label proteins so as to determine the elimination pathway followed. Alterations in this tagging system could be behind the abnormal accumulation of a-synuclein in nerve cells in PD patients.

Hence, we will promote different types of tagging on a-synuclein in cultured cells and compare the effect of these tags in the elimination of a-synuclein through the different cellular surveillance systems. Furthermore, we will also explore the possibility of modifying the tagging patterns by changing the intracellular levels of enzymes that perform the different types of tagging. In the future, new treatments of the disease could be designed to enhance the efficiency of these tagging mechanisms so as to favour the elimination of the toxic protein products.

5. The Michael J. Fox Foundation for Parkinson's Research will use its grant toward the Target Validation Initiative the Therapeutics Development Initiative Program.

The Target Validation Initiative is designed to accelerate the rate at which new Parkinson's therapies are brought to market.
The following is a complete list of researchers who were awarded grants under Target Validation 2007.

“Functional Inhibition of Ras GRF1 in the MPTP-lesioned NHP Model for Treating Levodopa-induced Dyskinesia”
Erwan Bezard, PhD, INSERM, France

“Validation of Metabotropic Glutamate-receptor Type 5 as a Target for the Treatment of L-DOPA-induced Dyskinesia in a Macaque Model of Parkinson’s Disease”
Angela Cenci-Nilsson, PhD, Lund University, Sweden

“Inhibition of c-Abl Tyrosine Kinase as a Novel Therapy to Prevent PD progression”
Syed Imam, MS, PhD, University of Texas Health Science Center

“Validation of Sirtuin 2 Deacetylase as a Therapeutic Target in Parkinson’s Disease”
Aleksey Kazantsev, PhD, Harvard Medical School

“Validation of Targets of Small Molecules that Ameliorate Alpha-synuclein Neurotoxicity”
Susan Lindquist, PhD, Whitehead Institute for Biomedical Research

“Targeting Urate: A Molecular Correlate of Both Risk and Progression in PD”
Michael Schwarzschild, MD, PhD, Harvard Medical School

“PGC-1 Alpha as a Neuroprotective Target in Parkinson’s Disease”
David Simon, MD, PhD, Beth Israel Deaconess Medical Center

“Validation of VPS41, a Protein Involved in Lysosomal Trafficking, as a Target for Parkinson’s Disease Therapy”
David Standaert, MD, PhD, University of Alabama, Birmingham

“Validation of Cathepsin D as a Target for Parkinson’s Disease Therapy”
Jianhua Zhang, PhD, University of Alabama, Birmingham


The Therapeutics Development Initiative is a program The Foundation launched as a key element in its strategy to "de-risk" preclinical Parkinson's disease research for biotech and pharmaceuical companies, thus expanding and catalyzing industry investments in the development of improved PD treatments and a cure.

The following is a complete list of Therapeutics Development Initiative awardees:

Somasunder Prasad Gabbita, PhD
P2D, Inc. (Cincinnati, Ohio)
Small molecule TNF-alpha inhibitors as neuroprotectant drugs for PD

Erik Miljan, PhD
ReNeuron Group PLC (Guildford, Surrey, United Kingdom)
Development of a Biodegradable Delivery Matrix Containing Dopaminergic Neurons Derived from Clinical Grade Mesencephalic Stem Cell Lines for the Treatment of Parkinson’s Disease

Bruce Moriomoto, PhD
Allon Therapeutics (Vancouver, British Columbia)
Evaluation of the Neuroprotective Peptide NAPVSIPQ in Models of Parkinson’s Disease

Peter Reinhart, PhD
Wyeth Research (Princeton, New Jersey)
LRRK2: Accelerated Pre-Clinical Development of a Novel Disease-modifying Therapeutic for Parkinson’s Disease

Stacy Markison Roth, PhD, and Sandra Lechner, PhD
Neurocrine Biosciences (San Diego, California)
Neuroprotective Effects of A2A Antagonists in Rodent Models of Motor Function and Dyskinesia

Gretchen Snyder, PhD
Intra-Cellular Therapies, Inc. (New York, New York)
Preclinical Evaluation of a 5-HT2A Antagonist for Treatment of L-DOPA-Induced Dyskinesias in Parkinson’s Disease

Ofer Wiser, PhD, and Benjamin Reubinoff, MD PhD
CellCure Neurosciences Ltd. (Jerusalem, Israel)
Dopaminergic Neurons Derived from Human Embryonic Stem Cells for Transplantation Therapy of Parkinson’s Disease

Brandon Wustman, PhD, and Sean Clark, PhD
Amicus Therapeutics (Cranbury, New Jersey)
Treatment of Parkinson’s Disease with AT2101, a Compound that Increases the Activity of Endogenous Glucocerebrosidase

Eti Yoles, PhD
Proneuron Biotechnologies (Ness-Ziona, Israel)
PN277: A Neurorestorative, Protective Product for Parkinson’s Disease

Steve Zhang, PhD
Sangamo BioSciences Inc. (Richmond, California)
Developing Engineered Zinc Finger Protein Transcription Factors as a Potential Therapy for Parkinson’s Disease

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

Project Title: Speech Treatment for individuals with Parkinson disease (PD)
Post-Deep Brain Surgery of the Subthalamic Nucleus (DBS-STN):
Systematic Development of a New Approach to Intervention

Lorraine Ramig, Ph.D., CCC-SLP
Jennifer Spielman, M.A., CCC-SLP
Angela Halpern, M.A., CCC-SLP
Leslie Mahler, Ph.D., CCC-SLP
National Center for Voice and Speech, Denver, Colorado
University of Colorado-Boulder

The need: Nearly 90% of individuals with PD have a speech or voice problem that can diminish quality of life. While surgical advances to treat PD, such as STN-DBS offer significant improvements in many body functions in individuals with PD, speech does not typically improve in these patients. In fact, there are reports that up to 30% of patients experience worsening of speech post-STN-DBS.

Today, LSVT is the only speech treatment for PD with level one evidence. Reports of application of LSVT to individuals post-STN-DBS have been mixed. While some reports suggest improvements, others suggest that some speech problems remain after LSVT. Most common complaints are that while patients do improve their volume and speech intelligibility following LSVT, labored articulation (motor problem), lack of carryover (internal cueing and learning problem) and resistance (sensory problem) remain. As a result, some patients do not have optimum communication outcomes. What is needed is an approach to address the specific speech problems in individuals post STN-DBS. Our years of experience developing LSVT position us well to take on this task.

Goal: The goal for this project is to begin to develop a systematic approach to speech treatment planning in individuals with PD post STN-DBS. We propose to develop a speech assessment protocol that will allow speech clinicians to optimize treatment outcomes with these individuals.

Plan: Our first step is to evaluate LSVT outcomes in three individuals with PD post STN-DBS compared with age, gender and severity matched individuals with PD (who had not been surgically managed) and an untreated PD control group. These data will be compared in order to identify post-treatment differences in these groups. A key element in our assessments will be the addition of detailed analysis of the most common communication breakdowns post-STN-DBS and their impact on speech treatment outcomes.

Based upon these findings, our next step will be a Phase 1 pilot study using multiple single subject designs. Eight individuals post STN-DBS will be studied across two months: pre-treatment (one week), LSVT (one month of treatment), post treatment 1 (one week), LSVT-DBS (one to two weeks) and post assessment 2 (1 week). Experimental speech data will be collected on these well-defined (stage of disease, medication, site of leads, stimulator settings) individuals.

A unique element of this work is that treatment related changes will be studied as they emerge during the course of treatment (not simply pre-post) in order to define the key breakdowns in individuals post STN-DBS. These key breakdowns will be used to systematically determine additions to be made to LSVT. Following standard LSVT, these individuals will participate in an LSVT-DBS “module” designed to specifically target the remaining challenges to their communication (e.g., motor, internal cueing, sensory). Post-treatment data will be collected after that LSVT-DBS module.

Outcome: These data will be used to inform an intake protocol tailored for planning speech treatment LSVT-DBS and outcome data following LSVT-DBS modules. These outcome data will be used to guide our further enhancement of DBS specific treatment modules.

Project Title: Proposal for Research on Pathological Gambling and Parkinson Disease

Indu Subramanian MD- Neurologist, Movement Disorders Specialist in Parkinson Disease
Timothy Fong MD- Psychiatrist, Gambling and Addiction Research
Russell Poldrack PhD- Psychologist, Behavioral Decision Making Research Group
Craig Fox PhD- Psychologist, Behavioral Decsion Making, Anderson School of Business

Recently, there have been published reports of patients with Parkinson disease who develop a gambling addiction while taking dopamine agonists. This may be statistically rare, (7% of patients on dopamine agonists), but when it does occur it can be devastating to the patient and family. This problem can lead to significant financial loss, marital discord, loss of employment and requires titration off of a dopamine agonist and may preclude deep brain stimulation (DBS). As a result, understanding why certain patients are vulnerable to develop this while others are not is a critical area to research. The premorbid personality of patients who develop Parkinson disease has been described as non-risk taking. Understanding changes in these risk-taking traits as patients develop the disease and with treatment is also a vital area of research.

A multi-disciplinary approach to this problem has been proposed at UCLA using expertise from the areas of neuropsychology, gambling addiction and neurology. We propose to systematically administer a battery of neuropsychological tests to three distinct populations: 1) Patients with Parkinson Disease 2)Patients with pathological gambling and c) Healthy controls. These tests have been shown to involve parts of the brain that control impulsivity and decision-making. This battery has previously been studied in normal healthy young controls at UCLA and the parts of the brain that are used while being tested have been shown with neuroimaging technology (fMRI). Funding is already in place to study the pathologic gamblers and healthy controls.

The neuropsychological testing takes one hour to complete and is computerized. We plan to recruit 60 patients with PD, 60 patients with Pathological Gambling and 60 healthy controls and then test them all with the same battery. The results of this testing will allow for comparisons between the three different groups which will inform us about the similarities and differences between the diseases. Parkinson disease patients who score similarly to pathological gamblers on these tests may represent a group that is at risk to develop gambling problems while on dopamine agonists.

This paradigm will be repeated over the course of the disease in Parkinson patients to see if differences in test results emerge as therapeutic interventions such as dopamine agonists or deep brain stimulation are added. We hope to predict from tests and other variables which patients may be at risk for this impulse control disorder. Additionally, fMRI testing of PD patients with abnormal computerized testing scores from the above study will be performed to further refine anatomical areas of interest and may lead to potential therapeutic strategies. FMRI for the control populations has already been performed and funding is already secured to scan the gambling group.

In order to support the PD portion of this proposal, resources will be needed for administration of the laptop testing on the 60 patients with PD and for scanner time to perform the fMRI scans on the subset of PD patients. Funds would also be needed for PD patient recruitment and reimbursement for patient parking.

Project Title: A Neurochemical Link Between Motor And Autonomic Deficits In Parkinson's Disease

Principal Investigator: Dr. Gay Holstein
Co-Investigators: Drs. Giorgio Martinelli And Victor Friedrich
Departments Of Neurology And Neuroscience
Mount Sinai School Of Medicine, New York

Difficulties with blood pressure regulation are common in Parkinson’s Disease patients, and may occur years before the emergence of the motor symptoms of the disease. The basis for this relationship between the neural control of blood pressure and the dopaminergic nigrostriatal pathway is not known. We hypothesize that a newly recognized neuromodulator involved in blood pressure regulation (IAA-RP) provides one basis for this association. The aim of the research is to identify the anatomical relationship between cells containing IAA-RP and those of the nigrostriatal projection, which utilize the classic neurotransmitters dopamine and GABA. We will test three hypotheses: (1) that IAA-RP is co-localized in dopaminergic neurons in substantia nigra, (2) that IAA-RP is present in GABAergic neurons in the striatum, and (3) that IAA-RP is present in dopaminergic and GABAergic terminals contacting GABAergic neurons in the striatum. The results of these experiments will provide the first evidence for a neurochemical link between autonomic and motor symptoms of Parkinson’s Disease. Since the blood pressure alterations typically precede the classic motor deficits, the results of this study are likely to contribute to our understanding of the earliest cellular changes that occur in the disease. They may provide a new approach for early diagnosis of the disease, as well as a new avenue for pharmacologic treatment.

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

Project Title: Mutation screening of genes for monogenic Parkinson’s disease in a large clinic-based cohort
Principal Investigators:  Birgitt Schuele, MD and J. William Langston, MD

Summary of work carried out with support of the Parkinson’s Unity Walk 2006:

Overview: The long-term goal of this project is to determine the mutation frequency of the currently known genes associated with parkinsonism in a movement disorders clinic-based cohort at the Parkinson’s Institute. The study was undertaken to answer critical questions regarding the necessity of genetic testing in a clinical setting and to help determine guidelines for the its use in the diagnosis of monogenic Parkinson’s disease and related disorders. This report provides an update on what is anticipated to be a several year project in which we hope to enroll ~1500 patients with various movement disorders and controls.

Progress to date: To date, we have enrolled a total of 736 subjects in our study and have identified 57 families with parkinsonism. All patients were seen at our Clinical Center at the Parkinson’s Institute.

We conclude that approximately 1% of our clinic population has parkinsonism and/or a related movement disorder due to an underlying genetic cause. Two cases were early-onset, both of which had PARKIN mutations.  Five had a strong family history, all of whom LRRK2 mutations. In addition, another patient proved to be an apparently sporadic LRRK2 carrier.  These results suggest that it is probably not yet warranted to carry out genetic testing in sporadic late-onset PD cases, but, as might be expected, familial cases have a much higher yield of mutations in the known genes for PD. While generalized clinical testing premature, there is no doubt that clinical and basic research on these rare genetic forms of parkinsonism can provide clues on underlying disease mechanisms in all forms of parkinsonism, and clues into factors determine severity, progression, and age at onset. Ultimately, all of the clues have a high probability of leading us to new strategies in therapy for both the genetic and non-genetic forms of the disease.  For these reasons, we are plan to continue and expand this important with for a second year with the support of Unity Walk Funding.

Background and Significance: Since the discovery of mutations in the alpha-synuclein gene, at least four other genes, Parkin, PINK1, DJ-1, and LRRK2, have been reported to cause monogenetic forms parkinsonism. Changes in Parkin, PINK1, and DJ-1 result in early-onset parkinsonism with an autosomal recessive inheritance pattern, whereas LRRK2 and alpha-synuclein typically show a dominant pattern of inheritance. To date, clinical detection of mutations in these genes has not had direct medical or therapeutic consequences for a patients and the role for genetic counseling in most of these cases has yet to be clearly defined. However, if a targeted therapy for these genetic forms becomes available in the future, it will be of outmost importance to detect these patients and carriers. Furthermore, a specific mutation in the LRRK2 gene has now been reported to be present 1.5% of all sporadic causes of PD, making it the most common form of typical parkinsonism in which we know the cause.

The goal of this study is to answer critical questions regarding the overall contribution of mutations in the different genes in a movement disorders clinic. Given the increasing number of mutations that can contribute to the a parkinsonian phenotype, and the increasing complexity of their manifestations, the time has come where we urgently need to define their exact contribution to Parkinson’s disease and related movement disorders. Gaining such knowledge is of obvious importance to better understanding the cause or causes of movement disorders; the results of this work also has direct implications for affected individuals, both in terms of potential therapeutic outcomes of research on specific mutations, and in terms of implications for future generations who may be at risk for disease. In addition, the research proposed here will allow for careful clinical studies of the phenotype, which could ultimately make it possible to predict a certain gene to be involved in the disease process. To answer these crucial questions, we plan to collect clinical data as well as blood for DNA extraction from all patients followed in the outpatient clinic of the Parkinson’s Institute, as well as a substantial number of controls.

This study is novel in that previously reported studies have been subject to referral biase or were consortia with highly selective referral criteria, so that these numbers may not reflect the mutation rate in the general population. While the planned study will not be truly population based, it will come closer to obtaining a realistic view of the genetic contributions to Parkinson’s disease and related disorders, as we plan to screen all clinic patients. Furthermore, with this large clinical and genetic screen, we have a realistic possibility of developing guidelines for neurologists to make predictions regarding molecular testing and would help to prioritize what genes need to be tested.

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