Funding from The Parkinson Alliance helped to finance the following Parkinson's research. Grantees were selected by scientific review committees of participating organizations. Updates will be posted, when available.
1. Alpha-synuclein (@-synuclein) is a small protein that has been found in the brain tissue (in Lewy bodies, the hallmark of Parkinson’s disease) of patients dying with PD. Altered or mutated @-synuclein is seen in tissue from some familial parkinsonisms, leading scientists to ask how the protein affects neurodegeneration. Dr. Mel Feany (Harvard) created transgenic fruit flies (drosophila) with human @-synuclein as animal models of such disorders and she and her group are using these inexpensive creatures to study genetic manipulation of the protein. Dr. Li Chen of this laboratory will use the grant award to try to find other proteins that interact with @-synuclein, hoping to delineate the pathways that lead to dopaminergic cell death. Learning more of the pathogenesis of human PD could lead to better knowledge of genes that cause susceptibility to parkinsonism, possibly even classic PD, as well as culling out possible targets for future therapy.
2. Direct and indirect pathways are the terms used by scientists to describe how the brain’s neurons send neurotransmitters via their axons. Some transmitters inhibit (slow) movement, others excite (speed up). The depletion of the neurotransmitter dopamine (DA) due to degeneration results in loss of movements and is thought to involve the biggest neural component of the striatum, medium spiny neurons that project the chemical GABA. Dr. Francois Gonon of Bordeaux (France) and his group will use his grant to record the activities of these neurons in anesthetized parkinsonian rodents in an attempt to determine the effects of various compounds on these pathways. They hope to show that drugs that enhance GABA transmission might prove useful as symptomatic therapy in human Parkinson’s disease patients.
3. Numerous groups have shown that amantadine hydrochloride (Symmetrel) is mildly helpful in relieving levodopa-induced dyskinesias (LIDs), probably due to its antagonism to NMDA receptors. Stronger such agents, however, cause somnolence, even psychoses. In an attempt to get around these problems, Dr. Penelope J. Hallett and her Harvard (Cambridge, Massachusetts) colleagues are using the awarded grant to examine the effects of inhibiting a specific phosphatase (an enzyme) in 6-OHDA-lesioned rat brain slices after administering a dopamine (DA) agonist. Their work will involve transfecting a new protein into the slices, using the new RNAi (interference) function to knock out a specified protein and fluorescence lifetime imaging (FLIM) to detect protein-protein interactions in neurons. Dyskinesias have been a limiting effect in a majority of patients’ receiving sufficient DA drug dosages to provide better mobility and it is thought that better understanding of the interplay between the DA system and the NMDA receptor system could lead to the discovery of compounds that would preclude them.
4. Several recent studies have shown that mutations in the gene LRRK2 appear to cause more cases of autosomal-dominant parkinsonism than has any other gene discovered to date. The LRRK2 gene encodes a protein called dardarin (so named by the Spanish group that first described it; the Basque word means tremor), and it is thought that dardarin may function as a protein kinase. These are enzymes that regulate a large variety of cellular processes. Dr. Sabine N. Hilfiker and her colleagues in Granada (Spain) will use their grant funds to explore the localization and enzymatic activity (dardarin is also thought to be present in Lewy bodies) of the protein and test their hypothesis that it may have a function in the survival of dopaminergic neurons, acting to promote the accumulation and aggregation of unfolded or mutated proteins such as alpha-synuclein and tau. Their work will be done in both human and animal tissues.
5. Two of the environmental toxins that are used to create animal models of parkinsonism, rotenone and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), are thought to work by inhibiting complex 1 of the mitochondria that, in turn, promotes oxidative stress and loss of dopaminergic (DA) neurons. Several groups have described a similar effect caused by a drug, metformin, presently approved to treat diabetes. Dr. Kari R. Hoyt and her associates at Ohio State University (Columbus) will use their grant funds to advance their work in mice that have been exposed to metformin via their drinking water. Reproducing the pathological effects of the compound (followed by behavioral effects) could provide the field with a new and inexpensive animal model of parkinsonism that would be useful in testing putative medications that might decrease the vulnerability of DA neurons to toxins that affect the mitochondria.
6. Drs. Daniel Levesque (and Claude Rouillard Laval University, Quebec City) will continue the work funded by their prior grant, last year, of using retinoic ligands (substances allied to retinoic acids) to modify levodopa-induced abnormal movements (LIDs) in MPTP-intoxicated monkeys. Having accomplished these modifications, the group will use this year’s funding to determine the pathways involved since it is thought that LIDs such as dyskinesias, so common in advancing PD patients, are influenced by potential chemical “partners” known as Nur 77 and Nurr 1. These, along with Nor-1, are identified as proteins that regulate the expression of numerous target genes that are involved in the dopaminergic (DA) system. This year’s work is the next step toward determining the appropriate compound to decrease or even preclude the LIDs that so greatly affect the quality of life of human patients.
8. Oxidative stress of multiple causes has been shown by many scientists to be involved in the pathogenesis of Parkinson’s disease. While the DATATOP study was not able to determine benefits from the antioxidant vitamin E alone or in combination with a monoamine-oxidase inhibitor, basic scientists have seen moderate benefits in animal cells and animal models of parkinsonism with the use of such compounds. Nor do we yet have data showing Lewy body or oxidative damage protection. Dr. LiPing Liang will use his grant to study yet another type of catalytic antioxidant, metalloporphyrins, in MPTP-parkinsonian mice and also in rat mitochondria slices. This class of antioxidants has been shown to have high lipid solubility and is thus better able to cross the blood-brain barrier resulting in more bioavailability. (One of the problems with vitamin E is that very little of a dose can cross the relatively intact barrier of the patient with PD.) His work will be done at the University of Colorado in Denver. Should his hypothesis prove out, the results could lead to development of candidate drugs for human clinical trials.
9. Mitochondria are considered the “powerhouse” or energy-producers of neuronal cells. In Parkinson’s disease, a large protein complex (Complex 1) has been found to be damaged, resulting in mitochondrial dysfunction. Numerous groups have shown that toxins that produce parkinsonisms in animal models do so by inhibiting Complex 1, resulting in oxidative stress and loss of dopaminergic (DA) neurons. Dr. Srinivas B.M. Mukunda and colleagues at the Buck Institute (Novato, California) are approved for grant funding to continue their work with DA rodent PC12 cells with induced depletion of glutathione. This is a tripeptide compound that is depleted in the parkinsonian brain and parallels disease severity. Molecular data indicate that oxidative stress plays a major role in neurodegeneration, with glutathione depletion being one of the early triggering events. More detailed knowledge of how Complex 1 is targeted for damage and how extensively that damage occurs, as well as how it leads to mitochondrial and blood-brain barrier defects, would provide the field with important information as to disease cause(s). In turn, such data could provide valuable insight as to terms of designs for neuroprotective as well as symptomatic therapy.
10. Should Dr. Meir Plotnik and his colleagues at Tel Aviv University (Israel) accomplish their grant funded goal of determining the basis of freezing of gait (FOG) in patients with Parkinson’s disease, it probably wouldn’t be long before appropriate therapy were devised. FOG is only too common in advancing patients; resistant in most patients to symptomatic medications and surgical procedures and a major handicap to patients who wish to live independently. His group, after some years of studying FOG, now wants to attempt to explain the mechanisms as a manifestation of uncoordinated bilateral motor performance of gait. They will compare PD patients experiencing FOG with patients who do not experience FOG and with a control group of age-matched healthy people. Computerized systems will be used to record and time both leg and hand movements, separately and together, during various novel motor tasks. They hope to finally determine if there is deterioration of the coordination between and among limbs during gait prior to the occurrence of a FOG episode. Identifying the pathophysiology of the symptom could lead to development of therapeutic counter-measures such as more appropriate physical therapy.
11. Among the compounds being tested as possible antiparkinson medications are those called A2A (adenosine) and NMDA (glutamate) receptor antagonists. These are two neurotransmitters that are thought to interact with the dopaminergic (DA) system and may have a role in the motor complications such as dyskinesias (LIDs) that affect so many symptomatically treated PD patients. Grant funds have been awarded to Dr. Alexia E. Pollack at the University of Massachusetts (Boston) so that she and her students can use the 6-hydroxydopamine (6-OHDA) rat model of parkinsonism to continue their attempts at determining how each of these neurotransmitters affects the ability of DA drugs to produce LIDs. It is their theory that the animals exhibit rotational behavior caused by “priming,” or repeated administration of DA drugs and that this known behavior suggests the cause of the motor complications seen in human patients. They will use numerous approved and experimental compounds in combinations, hoping that blocking behavioral sensitization in these animals will lead to a treatment strategy that is better tolerated by human patients who obviously will require DA replacement therapy over many years.