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.
The Parkinson’s Alliance awards a $25,000 grant to the University of Florida Movement Disorders Center to aid in Developing a Computerized Screening Tool for Parkinson’s disease patients interested in DBS
Although appropriate patient selection is widely recognized as the first and most important step of successful DBS therapy in Parkinson disease, there is no standardized assessment tool to accomplish this task. As a consequence, there may be confusion about referral criteria for DBS among general neurologists and other healthcare practitioners. These providers provide the majority of routine care to Parkinsonian patients. A recent paper reported that less than 5% of the patients referred for DBS surgery from private practice neurologists and general practitioners were appropriate and immediate candidates for DBS surgery (Okun et al., Neurology 2004; 63: 161-163). Tools are needed to help practitioners screen appropriate candidates for DBS.
We aim to link together in an integrated web-based computerized system a method for screening DBS candidates. The Florida Surgical Questionnaire for Parkinson Disease (FLASQ-PD) has been shown to be a useful triage tool for the workup of Parkinson disease surgical candidates. In addition to this screening tool this new computerized system will take into consideration possible ongoing behavioral and cognitive dysfunction such as depression, anxiety and dementia, which are common in Parkinson disease, and comprise absolute and relative contraindications for DBS surgery. These effects, if not screened for, can impede the success of the DBS procedure.
The purpose of this grant is to test COMPRESS (the comprehensive surgical screener for Parkinson’s disease) as a one-stop, easy-to-use method of quickly but thoroughly assessing a Parkinson patient’s ‘readiness for DBS surgery.
Parkinson's Disease and Movement Disorders Center Northwestern University
Impact of STN DBS on fine finger dexterity
Impairment of the size and speed of movements, specifically, fine finger dexterity is a significant part of PD-related disability. Currently, the mechanisms for the deterioration of these types of movements remain poorly understood. STN DBS significantly improves the overall degree of PD-related bradykinesia (slowness), but has a variable affect on fine finger dexterity (writing, repetitive finger movements) and does not improve these types of movements to the same extent as levodopa. We have recently discovered that patients with PD show two distinct abnormalities in the performance of paced repetitive finger movements: (1) a marked impairment in the performance of syncopated movements (movements initiated between beats of a metronome) and (2) a movement rate “barrier” characterized by the inability to maintain paced movements above about 2.25 Hz. We have also found that the impairment in syncopated movement can be reversed with anti-parkinsonian medications, but the high frequency movement impairment is unaffected by medication.
Why are these findings important?
These findings demonstrate that some aspects of movement performance in PD benefit from levodopa replacement therapy and others do not. The restoration of syncopated movement with levodopa suggests that these types of tasks are dependent upon dopamine, whereas the impairment in high frequency movements is due to dysfunction of other pathways. This means that a combination of therapies is likely required to restore movement towards normal. We will explore the possibility that a combination of levodopa and STN-DBS can be used to optimize performance.
We will compare and contrast the effects of levodopa and STN-DBS on syncopated and high frequency movements. We hypothesize that STN-DBS, as it is currently used, will not improve syncopated movements, but can be programmed to restore the ability of patients to make high-speed movements up to 3 Hz.
American Parkinson Disease Association, Inc.
Principal Investigator: Mel B. Feany, MD, PhD, Brigham and Women’s Hospital, Boston, MA
Title: Identification of Tyrosine-Phosphorylation Specific α-synuclein Binding Proteins.
Abstract: a-synuclein is a soluble, natively unfolded protein that is highly enriched in the presynaptic terminals of neurons in the central nervous system. It has a central role in the pathogenesis of Parkinson’s disease. The molecular mechanisms underlying the protective effect of tyrosine phoshorylation on a-synuclein toxity to dopaminergic neurons are unclear. We propose that tyrosine phoshorylation-specfic binding partners modulate the downstream toxic effectors of a-synuclien. To test the hypothesis, we will identify proteins that bind to tyrosine phosphorylated or deposphorylated a-synuclein and examine the role of these proteins in controlling a-synuclein toxicity. The specific aims are to identify proteins that interact with a-synuclein in a tyrosine phosphorylation dependent fashion and to validate genetically the role of interacting proteins in controlling a-synuclein toxicity.
Principal Investigator: Su Guo, Ph.D., University of California San Francisco, CA
Title: Toxicogenomic Analysis of Neurotoxin-induced Parkinson’s Disease in the Zebrafish Danio rerio.
Abstract: The behavioral symptoms associated with PD, such as tremor, rigidity and bradykinsia, are a result of selective degeneration of dopaminergic neurons in the substantia nigra. The proposal is to understand the molecular mechanism by which exogenous neurotoxins interact with endogenous genetic factors to cause degeneration.
The vertebrate model organism for genetics, zebrafish Danio rerio, will be employed.
The specific aims proposed are to carry out a detailed pathophysiological and behavioral analysis of a-synuclein transgenic zebrafish, to determine whether treatment with neurotoxins will enhance the neurodegeneration phenotype of α-synuclein transgenic zebrafish and lastly to identify genes and pathways that are altered upon exposure to these endogenous and exogenous neurotoxins..
Principal Investigator: Eunsung Junn, Ph.D., UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ
Title: Effects of DJ-1and DAXX Interaction on Cell Death.
Abstract: Investigations into cellular and molecular biology of genes that cause inherited Parkinson’s disease (PD), as well as, the downstream pathways that they trigger shed considerable light on the understanding fundamental determinants of life and death in dopaminergic neurons. Genetic data highlight the heterogeneity of the disease; the identification of particular therapeutic opportunities involving specific gene products could have implications for the wider PD population, since such molecular pathways likely coexist in complex harmony within nigral dopaminergic neurons. The proposal plans to investigate an unexplored cell death pathway in PD, which is modulated DJ-1 and links this pathway with a well-known dopaminergic neuronal stress. We hypothesize that DJ-1 can act as a molecular switch by binding to Daxx and inhibiting its interaction with ASK1, thus, preventing stress-induced ASK1 activation and subsequent apoptosis. The specific aims are to determine the role of DJ1 in the Daxx/ASK1-mediated cell death and to determine the role of Daxx/ASK1 pathway in MPP-induced cell death.
Principal Investigator: Weidong Le, MD, PhD, Baylor College of Medicine, Houston, TX
Title: Essential role of Iron in Proteasome Inhibitor-Induced Nigral Cell Degeneration.
Abstract: The cause of the neurodegenerative process in PD remains unclear, but evidence suggests that the failure of the ubiquitin-proteasome system (UPS) may play a major role in the pathogenesis of the disease. Iron is believed to be a key contributor to PD pathology by inducing aggregation of a-synclein and generating oxidant stress. We hypothesize that iron plays a key role in proteasome inhibitor-induced nigral pathology and that reducing iron overload may prevent dopaminergic degeneration and abnormal protein aggregation.
Principal Investigator: Felix Schweizer, Ph.D., University of California Los Angeles, CA
Title: A Role of Parkin in Synaptic Transmission.
Abstract: The proposal is to determine whether dysfunction of synaptic vesicle trafficking could contribute especially to early stages of Parkinson’s disease (PD). In particular we are interested in testing whether ubiquitin-modification of proteins by ubiquitin-ligases such as parkin can influence membrane trafficking directly by initiating or indirectly by regulating protein degradation by proteasome. We propose to test whether proteasome inhibition and parkin dysfunction interact on a molecular level or whether they represent alternate pathways of dysfunction relevant to Parkinson disease. The hypothesis being tested will determine if parkin regulates the trafficking of synaptic vesicles at the presynaptic nerve terminal and if it will increase synaptic vesicle trafficking in a parkin-null background and whether this effect is restricted to hippocampal neurons or can be reproduced in dopaminergic neurons.