The 2004 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) the American Parkinson's Disease Foundation; (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 2004 Parkinson's Unity Walk distributions. We will update the grants with progress reports as they are made available to us. In October 2005, updates to several grants were provided to us. Those updates are indicated below in red.
1. The American Parkinson Disease Association, Inc. is using its distribution to fund:
Grant Awarded To: Edwin Montgomery, Jr. MD
Project Title: Exploration of BG-Th-CTX System from the Standpoint of Non-linear Oscillatory Dynamics in Primates following the Administration of MPTP.
The Roger C. Duvoisin, MD Fellowships are intended as "special support money" for established scientists affiliated with U.S. research institutions and presently not working on Parkinson's disease. The applicants must be sponsored by a not for profit institution and the principal goal of the fellowship is to support new research ideas coming from established investigators.
Recent disappointment in fetal cell transplantation indicates that simple uncontrolled dopamine replacement in the basal ganglia is insufficient and agrues that a greater understanding of the physiology of the basal ganglia-thalamic-cortical (BG-Th-Ctx) system is critical for developing improved treatments. The remarkable success of deep brain stimulation (DBS) also emphasis the important of addressing physiological mechanisms. Studies of the mechanisms of action of DBS in conjunction of other studies strongly suggest that the current model of physiology and pathophysiology in insufficient.
Recent studies in our laboratory suggest a radical new concept in which the BG-Th-Ctx system is composed of many dynamic reentrant non-linear oscillators embedded in loosely coupled networks. Using new analytic techniques, neurons of ets BH-Th-Ctx have been demonstrated to be multi-stable; they sustain multiple and high frequency oscillations in their discharge probabilities. Further, neurons display specific states associated with sets of frequencies that then transition to new states analogous to bifurcations in complex systems of limit cycle oscillators.
These neurophysiological findings are strikingly similar to the mathematical properties of similar model systems. This strongly argues for the integration of recent advances in our mathematical understanding of complex non-linear systems with neurophysiological studies. Thus, we can develop a true theoretical neuroscience of the physiology and pathophysiology of these systems that could lead to rapid advances in the treatment of Parkinson's disease.
The proposed research will extend preliminary studies to a more vigorous exploration of the BG-Th-Ctx system from the standpoint of non-linear oscillatory dynamics in the non-human primate model of Parkinsonism following the administration of MPTP. These research efforts will integrate mathematical, computational and neurophysiological approaches. We will extend our use of resonance effects to multi-site paired-pulse stimulation combined with mathematical and computational studies to determine the dynamical physiological architecture of the BG-Th-Ctx and the pathophysiological mechanisms leading to disability.
2. The National Parkinson Foundation is using its distribution to fund the following:
Grant Awarded to: Dr. Srinivas Bharath Muchukunte Mukunda, Buck Institute,CA.
Project title: Peroxynitrite-mediated oxidative damage of mitochondrial complex I in dopaminergic neurons: Implications for Parkinson's disease
During Parkinson's disease, accumulation of "toxic" forms of oxygen and nitrogen (also called as reactive oxygen or nitrogen species) might damage different biological molecules ultimately degenerating the powerhouse of the cell, that is, the mitochondria. The main target of such damage is an enzyme within mitochondria called "complex I". This event might be one of the main reasons for the loss of brain cells during Parkinson's disease. The main aim of the current study is to investigate the mechanism underlying the damage of complex I and also to find out which part of the complex is getting affected by this toxic insult. This would help both in understanding the disease and in improving strategies of therapy.
October 2005 Project Update:
a) Purification and MS analysis of CI from mouse brain and dopaminergic N27 cell line (Reference: manuscript 1 in section 6): Studies using in vitro and in vivo PD models or human tissues have demonstrated a selective inhibition of CI that affects normal mitochondrial physiology leading to neuronal death. In an earlier study, we demonstrated that GSH depletion in dopaminergic cells leads to CI inhibition via cysteine thiol oxidation. CI, a 980-KDa multimeric enzyme spanning the inner mitochondrial membrane comprises of at least 45 subunits. As a prerequisite to investigating modifications to CI using a rodent disease model for PD, we developed two independent rapid and mild isolation procedures based on sucrose gradient fractionation and immunoprecipitation to isolate CI from mouse brain and a cultured rat mesencephalic dopaminergic neuronal cell line. Both protocols are capable of purifying CI from small amounts of rodent tissue and cell cultures. Blue Native gel electrophoresis, one and two-dimensional SDS-PAGE were employed to assess the purity and composition of isolated CI followed by extensive MS characterization. Altogether, 41 or 45 rodent CI subunits achieved MS/MS sequence coverage. To our knowledge, this study provides the first detailed mass spectrometric analysis of neuronal CI.
b) Role of PN mediated nitration of tyrosine residues in GSH depletion mediated CI inhibition in dopaminergic neurons (Reference: manuscript 2 in section 6): Recent observations have indicated that oxidative damage to CI via naturally occurring free radicals such as PN leads to modification of tyrosine and/or cysteine residues resulting in CI inhibition. It is also known that GSH detoxifies PN. Using the sucrose gradient method, we detected in CI-enriched fractions from a GSH-depleted dopaminergic cell line two bands corresponding to ~25kD and ~30kD polypeptides which demonstrate anti-nitrotyrosine immunoreactivity. This clearly suggests that possible involvement of protein nitration by PN in GSH depletion mediated CI inhibition.
Grant awarded to: Dr. Vincenzo Bonifati, MD, PhD
Project Title: Genetic determinants of early-onset Parkinson's disease
In most cases, Parkinson's disease (PD) appears after the age of 60, and it is a sporadic disease (in other words, there are no other affected family members). In these common, late-onset forms, the cause(s) of the disease remain(s) unknown. In rare cases, especially those with a very early onset (before age of 40), PD might be inherited, meaning that a genetic defect might be at the roots of the disease in these rare forms.
The aim of our project is to study the DNA samples donated from many patients with very early-onset PD and their relatives, in order to identify novel genetic defects causing the disease. By unraveling the genetic defects causing these rare forms, we hope to understand better and faster the mechanisms underlying the common, non-hereditary forms of PD, ultimately leading to the identification of novel targets for curative approaches.
October 2005 Project Update:
DNA samples and clinical/genealogical data were collected from 323 PD probands (220 early-onset), 120 affected and 214 unaffected relatives, totaling 657 samples. A comprehensive analysis of the two recently discovered PD-causing genes, PINK1 and LRRK2, was performed. By analyzing PINK1 in 134 early-onset cases, we identified several novel mutations, provided frequency estimate for mutations, and a detailed phenotypic description of the largest series known so far with PINK1 mutations. [Neurology, full-length paper, in press]
We analyzed all the 51 exons of LRRK2 in 61 dominant families; we identified a novel mutation (G2019S) in ~6% of the families [Di Fonzo et al, Lancet 2005] and other mutations. In an independently collected series, we identified G2019S in 13 of 629 PD probands. We provided accurate estimate of the G2019S frequency according to PD onset age and pattern of familial aggregation. The study delineated G2019S as the most common genetic determinant known so far in familial PD of both early- and lateonset; the mutation was also found in a few sporadic cases; last, we provided strong evidence for the origin of this mutation from a common, ancient founder. [Submitted to J Med Genet]
In a large Brazilian kindred (16 early-onset PD) linkage/haplotype analyses suggested the involvement of parkin and a novel mutation was identified. The mutation (IVS1+1C/T) disrupts mRNA splicing, as demonstrated by the absence of parkin transcript in the patients. [Manuscript in preparation] Novel chromosomal regions linked to early-onset, autosomal recessive PD were identified in our genomewidescreen [unpublished data]. Further consanguineous and non-consanguineous families were genotyped, and two regions were refined with the strongest evidence for linkage to PD. Mutation analysis of positional candidate genes from these critical regions is in progress.
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: Dr. David S. Park
Project Title: Neuronal Inflammation
Neuronal inflammation is a topic of much research these days, and is thought to be a possible cause of dopaminergic cell loss. If compounds that cause inflammation of microglia (neuronal support cells) are part of the cascade pathway to neuronal death, it may be possible to inhibit these compounds and provide neuroprotection. Dr. David S. Park (University of Ottawa) will use the MPTP-mouse model of parkinsonism to try to determine if a specific inflammatory, IFN-gamma, already found to be elevated in sera of PD patients, acts with the neurotoxin MPTP to induce further cell death. Learning whether IFN action is on microglia alone, or on neurons as well, would suggest additional experiments that might pin down where intervention in the cascade might be possible.
October 2005 Project Update:
Dr. David S. Park and his colleagues at the University of Ottawa received PDF funds for a study to try to determine if a specific inflammatory agent, interferon-gamma, is a cause of death to microglia (neuronal support cells) only or also to neurons. They chose this particular inflammatory because it has been found to be elevated in PD patients.
Using mice who lacked the necessary brain receptors for interferon-gamma with wild-type (normal) mice as a control group, the team administered a known neurotoxin, MPTP, and found reduced losses of nigral cells as well as those indicators of parkinsonism, the enzyme tyrosine hydroxylase and striatal dopamine transporter density in the transgenic animals. These results indicated that interferon-gamma doesn’t affect dopaminergic neurons, but works on the support activities of microglia. The data suggest that targeting microgliosis (inflammation of microglia) through the use of substances that modulate levels of interferon-gamma may prove useful in neuroprotection in early-stage patients.
Grant Awarded To: Dr. Joelle Van der Walt
Project Title: Study of FGF20, Growth Factor
In genetic disorders, many genes have one normal version (wild-type), while other genes exhibit polymorphism (literally many forms), describing the information at particular loci on the gene. Called SNPs (and pronounced snips), these can now be typed and examined in the genes of members of a specific family in order to better understand the family's disorder. The PDF is supporting Dr. Joelle van der Walt (Duke University) in her study of FGF20, a growth factor that seems to be required for the health of nigral dopaminergic neurons, though how it protects is not yet known. She plans to examine numerous SNPs taken from individuals in a large parkinsonian family to learn if and how these might affect FGF20 expression, and thus learn more about the degeneration of cells seen in PD. Her hope is that her results would provide information leading to protective therapy.
October 2005 Project Update:
Dr. Joelle van der Walt and her colleagues at Duke University (Morris K. Udall Center) were awarded funds to study a growth factor (FGF20) that is thought to be required for the health of dopaminergic neurons in the substantia nigra, an area of the brain affected by Parkinson's disease and other parkinsonisms. They looked at the effects of FGF20 in PC12 cells grown under varied conditions, and then looked at its effects in SNPs (polymorphisms) taken from individuals in a large parkinsonian family as well as from heterozygous (classic PD) cases. They were unable to detect significant differences between the types of transcripts and thus have not elucidated the function of these SNPs. Joelle van der Walt is hopeful, however, that the data will provide further information regarding the expression of FGF20 in nigral cell survival.
This is a step in a good direction, but needs additional studies before neuroprotection is indicated.
Dr. van der Walt's research focus is the molecular genetics of Parkinson's disease. Her special expertise is in mutation analysis of nuclear and mitochondrial candidate genes.
5. The Michael J. Fox Foundation for Parkinson's Research will use its grant toward the Community Fast Track 2003 initiative. Fast Track is an investigator-initiated, peer-reviewed program that considers a broad range of research applications relevant to the cure, cause, prevention or improved treatment of Parkinson's disease. It was designed to support cutting-edge research, while streamlining the grant making process and compressing the timeline in which scientist receive award money. For more information see its website at www.michaeljfox.org.
6. The Parkinson Alliance is proud to be part of The Michael J. Fox Foundation for Parkinson's Research "Community Fast Track 2003." The Alliance will use its grant toward this program.
Under this program, researchers are invited to submit investigator-initiated grant applications to conduct research relevant to the cure, cause, prevention or improved treatment of Parkinson's disease (PD) and its complications. The intent of this RFA is to stimulate novel, innovative, and/or high-impact approaches to the field of Parkinson's disease as well as to fill funding gaps missed by more conventional funding sources. It was designed to support cutting-edge research, while streamlining the grant making process and compressing the timeline in which scientist receive award money. For more information, see its website at www.parkinsonalliance.org.
7. The Parkinson’s Institute is using its distribution to fund the following:
Project Title: a-synuclein aggregation, microtubule dysfunction, and neuritic degeneration in neuronal models of synucleinopathies
Principal Investigator: Seung-Jae Lee
Abstract: In the current study, we investigate the mechanism of a-syn-induced Golgi fragmentation with the premise that this might lead to the potential pathogenic target of a-syn. Here, we report that the pattern of a-syn-induced Golgi fragmentation is similar to that caused by the MT-disrupting agent nocodazole. We also show that a-syn overproduction causes the disruption of the MT network, neuritic degeneration, and a -syn/tublin co-aggregation within the degenerating neurites. We propose that MT dysfunction plays a key role in a-syn-mediated neurodegeneration that leads further down-stream effects, such as Golgi fragmentation and neuritic degeneration.
October 2005 Project Update:
In this study the researchers demonstrated that a-syn over expression causes MT dysfunction and further downstream degenerative effects in neuronal cells. From various findings in the study it is proposed that MT dysfunction and subsequent cellular impairment, e.g. nueritic degeneration and Golgi fragmentation, might be critical components in the mechanism of a-syn mediated neurodegeneration. Determining the precise mechanism by which abnormal a-syn disturbs MT integrity will provide insight into the early pathogenic mechanism of PD and other synucleinopathies.