The 2001/2002 Parkinson’s Unity Walk Funds Research Grants
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3. The Parkinson Alliance is using its distribution to help fund the R21 Fast Track Grant Program.
The Parkinson Alliance is proud to be part of an unprecedented collaboration with the National Institutes of Health (NIH) and private Parkinson's organizations to jointly fund a program of $11 million in Parkinson's disease research grants. The Alliance will use its grant towards funding the R21 Fast Track Grant Program, which awarded 35 two-year grants making it the largest initiative that NIH has ever taken in the history of Parkinson's disease research. The awards were made through an innovative streamlining of the NIH's normal grant process. This program is funding a large body of excellent research, attracting new investigators to the field of Parkinson’s disease research, and establishing a precedent for a public-private partnership that will lead to future initiatives. The goal is to stimulate novel, or high impact approaches relevant to the cure, cause, prevention, or improved treatments of Parkinson's disease. Other organizations helping to fund this program include The Parkinson's Disease Foundation, the National Parkinson Foundation, the Parkinson's Unity Walk, and The Michael J. Fox Foundation for Parkinson's Research. For a list of researchers who have been awarded grants, see http://www.parkinsonalliance.net/news/fasttrack.html.
4. Parkinson’s Disease Foundation is using its distribution to help fund the following:
Structural Basis for the Parkin Inactivation by Mutations Causing AR-JP. This grant is being researched by Brenda A. Schulman, Ph.D. at St. Jude Children’s Research Hospital in Tennessee. Summary: Dr. Schulman will be using her grant to study the structure and mechanisms of action of parkin, a protein that functions abnormally due to gene defects, and may be the clue to understanding early Parkinson’s disease. Parkin is a ubiquitin ligase, a protein that plays an important role in cell metabolism. Specifically, Dr. Schulman will examine how mutations in the parkin gene disrupt its function as a ubiquitin ligase. She expects her findings to provide a starting point for future efforts to restore ubiquitin ligase activity in the brains of patients with PD, which could, in turn, lead to potential treatments of the disease.
Progress Report update January 2004
Brenda A. Schulman, Ph.D. "Structural Basis for Parkin Inactivation by Mutations Causing AR-JP"
Parkin is a gene whose protein interacts with numerous other proteins and inhibitors in brain tissue. When parkin mutates or misfolds, it has been found by many laboratories to be either disease-causing (such as in families with autosomal recessive parkinsonism) or protective (rescuing cells from the neurotoxicity of other mutated proteins such as alpha-synuclein). Parkin's activity is dependent upon how the gene mutates or misfolds.
With funding from the PDF, Dr. Breanda A. Schulman and her group have examined the interactions between parkin and its many "partners in crime," so to speak, in the hope of better delineating the biochemical pathways that have been found to be involved in the young-onset, familial forms of parkinsonism. While they have not yet been able to specify exactly how these pathways might be involved in classic (sporadic) PD, they have indentified a number of leads using x-ray crystallography that show weak bonds between parkin and, for example, @-synuclein, signaling that gene dosages (the amount of proteins made by genes) may play such a role.
Is Parkinson’s Disease Caused by Misfolded Conformations of Alpha-Synuclein? This grant is being researched by Jay Winkler, Ph.D. at the California Institute of Technology. Summary: Dr. Winkler proposes to study the formation of alpha-synuclein, a protein that is present in Lewy bodies, the abnormal intraneuronal inclusions that are found in PD brains. He expects his study of the way alpha-synuclein folds itself to shed light on its role in PD. If misfolded alpha-synuclein causes the disease, there will be a search for substances that can inhibit this process. Such discoveries could later be the basis for medications that could arrest the course of the disease.
Progress Report update January 2004
Jay Winkler, Ph.D. "Is Parkinson's Disease Caused by Misfolded Conformation of Alpha-synuclein?"
Dr. Winkler was provided with funds to support his studies of the involvement of alpha-synuclein in the pathogenesis of Parkinson's disease and several familial parkinsonisms. Alpha-synuclein is the first (a=alpha=first alphabet letter) in a family of insoluble proteins that may aggregate in brain tissue. This one is a small protein that has been found in clumps in autopsied PD brains in the form of Lewy bodies, long considered proof of the existence of PD. When @-synuclein misfolds and accumulates during usual brain processes, these aggregates form and are thought to damage neurons. It has been determined that certain genes and environmental factors, such as rotenone and MPTP, can increase this misfolding process.
It is known that @-synuclein interacts with tyrosine hydroxylase (TH), the enzyme that converts levodopa to dopamine both in brain and in laboratory experimental cell lines and that the protein also inhibits TH activity, thus inhibiting the formation of necessary dopamine. According to Dr. Michael Zigmond (University of Pittsburgh), overexpression of @-synuclein dramatically reduces TH activity.
What all this is leading to is that Dr. Winkler and his group have probed wild-type (normal) and mutant forms of @-synuclein in order to map the protein and determine its pathogeneic role in the familial or early-onset forms of parkinsonism in the hope that these date will provide clues to the pathogenesis of classic Parkinson's disease as well.
5. The National Parkinson Foundation is using its distribution to fund the following:
—NMR Studies of Synucelin Dopamine Interactions. This grant is being researched by David Eliezer, Ph.D., Cornell University, NY.
Summary: The protein Alpha-Synuclein is believed to play an important role in the pathogenesis of Parkinson’s disease. There is significant evidence suggesting that some aspect of Alpha-Synuclein aggregation is important in the development of PD. Recently, it has been reported that oxidized derivatives of dopamine and other catecholamines interact preferentially with Alpha-Synuclein , forming adducts, and influencing its aggregation by accelerating initial oligomerization and protofibril formation while retarding mature fibril formation (Conway et al. 2001). This result suggests an explanation for the fact that it is primarily dopaminergic neurons that die in PD, and also provides a possible explanation for the link between oxidative stress and PD. This proposal aims to investigate the mechanism by which dopamine modification influences the structure and aggregation of Alpha-Synuclein using biophysical methods including high resolution solution state nuclear magnetic resonance (NMR) Spectroscopy. The specific aims are: (1) identify the locations of dopamine modification of Alpha-Synuclein; (2) characterize the effects of dopamine modification on the structural properties of free monomeric Alpha-Synuclein; and (3) characterize the effects of dopamine modification on the structural properties of Alpha-Synuclein bound to lipid-mimetric detergent micelles.
Progress Report update November 2003
The objects of this proposal were:
To identify the locations of dopamine modification of _-synuclein; to characterize the effects of Dopamine modification on the structural properties of free monomeric _-synuclein; to characterize the effects of dopamine modification on the structural properties of _-synuclein bound to lipid-mimetic detergent micelles.
In pursuing these aims were able to confirm a covalent interaction between _-synuclein and dopamine under oxidizing conditions, and to use high resolution NMR spectroscopy to show that this interaction does in fact perturb the structural properties of free monomeric _-synuclein. We have made progress in identifying the locations of dopamine modifications of _-synuclein, but have not completed this task. We have also prepared _-synuclein constructs that will limit such modifications to specific sites to aid in accomplishing aims 2 and 3.
We have established the methodology for characterizing in detail the effects of dopamine modification on the structures of free and lipid bound _-synuclein, which will be applied once we are able to complete the identification of, and to control, sites of modification.
No publications resulted directly from this work during the course of the grant year. However, our group did publish a paper in a related area.
Bussell, R., Jr. & Eliezer, D. (2003). A structural and functional role for 11-mer repeats in alpha-synuclein and other exchangeable lipid binding proteins. J. Mol Biol 329, 763-78.
DAVID ELIEZER, Ph.D.
Weill Medical College
Cornell University
New York, New York
— Microglia Activation in Parkinson’s Disease. This grant is being researched by Glenda Halliday, Ph.D. of Prince of Wales Medical Research Institute, NSW, Australia.
Summary: The grant seeks to systematically document the microglial and associated neuronal changes in the various regions we have already identified as undergoing degeneration at different stages in PD. Our recent data indicates that there is approximately 70% loss of non-parvalbumin-positive neurons in the caudal intralaminar thalamus and 90% loss of non-SM132-positive pyramidal neurons in the pre-supplementary motor cortex in patients with PD. The severity of selective neuronal loss in these regions rival that observed in the substantia nigra in the same cases, yet there is little deposition of Alpha-Synuclein in these non-dopaminergic neuronal populations. In contrast, neurodegeneration in the amygdala and associated limbic cortices (non-dopaminergic brain regions) occurs only late in the disease course and is associated with significant Alpha-Synuclein deposition. Further study of these regions should determine whether activated microglia are: (1) a common phenomenon in all areas of neuronal death in PD; (2) increased in regions with Alpha-Synuclein deposition; and (3) an early or late event in disease pathogenesis. This project seeks to determine the contribution of microglia to the more widespread neurodegeneration characterizing PD. If the microglia are a consistent feature in areas of neuronal cell loss, the successful treatment strategies recently directed at microglia activation in animal models of PD may have relevance to the human condition.
Progress Report update November 2003
The pathogenesis of Parkinson’s disease is unknown, but Nigral degeneration and depigmentation appears to involve a significant inflammatory process. Current animal models implicate an immune-inflammatory process involving early microglial activation, a response ameliorated by anti-inflammatory medications. This study analyzes the immune-inflammatory process in the brains of patients with idiopathic Parkinson’s disease (PD, N=13) compared with controls (without neurological or neuropathological disease, N=12). Four of the PD cases died prematurely at early Hoehn and Yahr stages of disease (stages 2 and 3). Formalin-fixed tissue samples were taken from the substantia nigra (affected) and primary visual cortex (unaffected) and cut at 20 microns on a cryostat. A battery of immunohistochemical markers were used (GFAP, HLA-DR, HLA-ABC, CD3, CD4, CD8, CD19, CD56, and immunoglobulin G). Previously reported selective upregulation of MHC class 2 in activated microglia within the PD substantia nigra was confirmed; however, only rare lymphocytes were observed. Also, a proportion of pigmented Nigral neurons in the PD cases stained positive of immunoglobulin G. No similar staining was observed in the visual cortex. These results suggest that microglial activation occurs early in the degenerative process (present by stage 2 disease) and that the tissue changes in the substantia nigra appear relatively restricted at these and subsequent disease stages (neuronal depigmentation, neuronal degeneration). Of course, it is not possible to visualize the earliest degenerative changes in human PD but overwhelming cellular inflammatory infiltrates appear unlikely. Our results show that immunoglobulin G may be more important that previously suspected for microglia transformation to selectively lyse and phagocytose the pigmented Nigral neurons in this region.
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