The Morris K. Udall Center of Excellence for Parkinson's Disease Research, University of California, Los Angeles

Director: Marie-Françoise S. Chesselet, M.D.

Website: http://www.bri.ucla.edu/bri_research/Udall.asp

Central Theme

The central unifying theme for the UCLA Morris K Udall Parkinson disease Center of Excellence is uncovering the mechanisms of progression of dysfunction of both motor and non-motor symptoms of Parkinson’s disease, and the application of these findings to the development of new treatments for PD.

Center Structure

The research core of the UCLA Morris K Udall Parkinson Disease Center consists of five highly collaborative and multi-disciplinary research projects:

• Project 1 (Chesselet and Yang) examines the time-course of behavioral, anatomical, and molecular aspects of motor and non-motor pathology using genetic mouse models of PD
• Project 2 (Maidment and Schweizer) focuses on the progression of dysfunction in dopamine and related neurotransmitters in cellular and PD mouse models,
• Project 3 (Levine) studies and compares the early underlying alterations in pre-and post-synaptic communication in different genetic models of PD
• Project 4 (Schweizer) examines the role of parkin and its binders in progression of cellular dysfunction and cell death
• Project 5 (Vickrey and Ritz) evaluates the role of environmental, behavioral, and social factors in the development and progression of PD motor and non-motor symptoms, and their relative contributions to patient health-related quality of life measures

The administrative core continues to support the goals of the Center by organizing the various activities of the Center, including regularly scheduled meetings of the Center investigators, joint PI-post-doc meetings, and monthly seminars where each member of the group presents their ongoing work to the PD research community. The annual Udall symposium features talks by the Center PI’s and a poster session open to the public. The administrative core is also responsible for maintaining the Center website, organizing enrichment activities for undergraduate researchers in the Center laboratories, as well as an annual PD undergraduate poster session.

The Mouse Genetics core is responsible for breeding, maintaining and supplying the investigators at the Center with mice, as well as generating new genetic mouse models of Parkinson’s disease.

Recent Significant Advances

• We have continued to characterize the non-motor deficits in the thy1-aSYN mouse model of PD in more detail, demonstrating profound alterations in olfaction, colonic function, and baroreceptor function in these mice, similar to the observed cardiovascular problems in PD patients. We have also uncovered significant cognitive deficits in these mice that can be used to test treatments for cognitive deficits, a major unmet need for the treatment of PD. Furthermore, we have found evidence of inflammation and regionally specific elevation of cytokines in the brains of these mice. The battery of behavioral assessments developed in this mouse model is currently being used to test potential new treatments for PD and 3 preclinical trials have been completed while two are ongoing.
• We have generated a new line of alpha-synuclein overexpressing transgenic mice in which the protein is expressed under its own natural promoter, in order to produce a more relevant model of PD. We are characterizing these mice using motor and behavioral tests at various ages, as well as the accumulation of proteinase-K resistant alpha-synuclein in various brain regions.
• Both alpha synuclein and parkin are implicated in the ubiquitin-proteosome system. By blocking the ubiquitin-proteosome system to disrupt synaptic transmission, we obtained electrophysiological evidence that UPS blockers seem to have a presynaptic site of action, and that the mechanism of modulation of synaptic transmission through ubiquitination seems to be through modification of protein activity rather than its half-life.
• We have shown that overexpression of alpha-synuclein in our mouse model leads to a decrease in neurotranmitter release at the corticostriatal synapse, and an alteration in presynaptic plasticity in this pathway, at an early, pre-manifest stage, suggesting that dampened corticostriatal synaptic activity could lead to reduced movement
• We analyzed the diagnostic accuracy of two different depression assessment scales used in PD research (PHQ-9 and GDS-15) and continue to evaluate the quality of measurement of other non-motor outcome instruments, as well as analysis of insomnia, depression and cognitive deficits. These analyses will become part of a comprehensive and specific tool for assessing health related quality of life in PD patients.
• We have completed a second round of examination and data collection from a cohort of PD patients in the Central Valley of California, to assess whether and to what extent the development and rate of progression of motor and non-motor manifestations (eg, cognitive impairment and depression) are influenced by environmental, behavioral, and social factors, including pesticide exposure, physical activity, stress, coping, and social support.

Available Resources

PD Mouse Repository

The mouse genetics core makes newly created genetic models available to the scientific community after publication as per NIH guidelines and with standard Material Transfer Agreement.

Plans for the Coming Year

We will continue to examine the underlying cellular and molecular mechanisms responsible for early, pre-mainfest dysfunction in PD, by using anatomical, electrophysiological, molecular, and epidemiological studies, with a focus on the non-motor manifestations of the disease in both human patients and animal models.

• We will expand the characterization of autonomic, affective, and cognitive deficits in both the Thy1 and BACsyn mouse models, characterize the olfactory deficits, and investigate the role of inflammation in disease development and progression
• We shall continue to use a number of behavioral, motor, and anatomical measures in these mouse models in pre-clinical testing of potential therapeutic drugs for PD
• We will continue to examine the nature of dopamine homeostatic dysregulation using microdialysis to determine whether it is a result of increase basal vesicular release of DA or from a deficit in packaging and vesicular transport into the cells.
• The mechanisms of altered synaptic plasticity in the corticostriatal pathways will be further studied using single-cell recordings and gene expression studies to identify the relevant pathways in the underlying synaptic alterations which precede the appearance of motor symptoms.
• We will continue the analysis of the PD cohort and of relevant information about environmental, behavioral, and social factors and rate of progression of motor and non-motor symptoms. We will be completing the analysis of data obtained with the new health-related quality of life measure designed to accurately evaluate motor and non-motor disease progression and serve as a measurement tool for translation studies evaluating the impact of future PD therapies.

Select Recent Publications

Richter F. Meurers B., Zhu Z., Chesselet M-F. Hemoglobin alpha and beta chains are highly expressed in neurons and transcriptionally regulated by rotenone. J Comp Neurol. 515(2009)538-47. PMID: 19479992

Steele A, Zhou Z, Jackson W, Zhu C, Auluck P, Moskowitz M, Chesselet MF, Lindquist S. Context dependent neuroprotective properties of prion protein (PrP). Prion. (2009) Oct 16;3(4) 240-9. PMID: 19901559

De Deurwaerdère P, Le Moine C, Chesselet MF. Selective blockade of serotonin2C receptor enhances Fos expression specifically in the striatum and the subthalamic nucleus within the basal ganglia. Neurosci Lett. 469 (2010) 251-55. PMID: 20004702

Rinetti G and Schweizer FE (2010). Ubiquitination acutely regulates presynaptic neurotransmitter release in mammalian neurons. J. Neurosci. (2010) 30(9):3157-66. PMID: 20203175

Maidment NT, Lam HA, Wu N, Cepeda C, Ackerson LC, Masliah E, Levine MS (2010) Overexpression of ?-synuclein increases extracellular dopamine concentration and alters dopamine modulation of synaptic function in mouse striatum. Submitted for publication

Wu N, Joshi PR, Cepeda C, Masliah E, Levine MS. Alpha-synuclein overexpression in mice alters synaptic communication in the corticostriatal pathway. (2009) Jun; 88(8): 1764-76. PMID: 20029978

Brown C, Cheng EM, Hays RD, Vassar S, Vickrey BG. SF-36 includes less Parkinson’s disease-targeted content but is more responsive to change than two PD-targeted health-related quality of life measures. Quality of Life Research 2009;18:1219-1237. PMID: 19714487

Thompson AW, Liu H, Hays RD, Katon WJ, Rausch R, Diaz N, Vassar SD, Vickrey BG. Diagnostic accuracy and agreement across three depression assessment instruments for Parkinson Disease. [will be “In Review” by end of Jan 2010]

Jacob EL, Gatto NM, Thompson A, Bordelon Y, Ritz B. Occurrence of Depression and Anxiety prior to Parkinson’s Disease. Parkinsonism Relat Disord. 2010 Jul 30. PMID: 20674460

Costello S, Bordelon Y, Bronstein J, Ritz B. Familial Associations of Alzheimer Disease and Essential Tremor with Parkinson Disease. Eur J Neurol. 2010 Jun 1;17(6):871-8. PMID: 20236304

Gatto N, Cockburn M, Bronstein J, Manthripragada AD, Ritz B. Well Water Consumption and Parkinson’s Disease in Rural California. Environ Health Perspect. (2009) 117(12):1912-8 PMID: 20049211

Manthripragada A, Cockburn M, Costello S, Bronstein J, Ritz B. Paraoxonase 1, agricultural organophosphate exposure, and Parkinson disease. Epidemiology. (2010) 21(1):87-94 PMID: 19907334

Plaitakis A, Latsoudis H, Kanavouras K, Ritz B, Skoula I, Mastorodemos V, Papapetropoulos S, Zaganas I, Hadjigeorgiou GM, Spanaki C. Gain-of-Function Variant in GLUD2 Glutamate Dehydrogenase Modifies Parkinson’s Disease Onset. Eur J Hum Genet. (2010) Mar;18(3):336-41. PMID: 19826450

Ritz B, Manthripragada A, Costello S, Lincoln SJ, , Farrer M, Cockburn M, Bronstein J. Dopamine Transporter Gene Polymorphisms Interact With Pesticide Exposures To Increase Parkinson Disease Risk. Environ Health Perspect. (2009) 117(6):964-9 PMC ID: PMC2702414

Costello S, Wahner A, Bronstein J, Cockburn M., Zhang X, Ritz B. Paraquat and Maneb exposure and Parkinson’s disease in the California Central Valley. Am J Epidemiol. (2009) Apr 15;169(8):919-26.

Public Health Statement

Investigators at the UCLA Morris K Udall Parkinson Disease Center of Excellence use a collaborative and multi-disciplinary approach to elucidate the cellular and molecular events that occur prior to neuronal degeneration and the manifestation of motor symptoms in Parkinson’s disease, in order to advance the development of therapeutics which can slow or halt progression before there is significant cell loss.

We continue to collect and analyze a wealth of data from our large-scale epidemiological study, which examines the progression of motor and key non-motor symptoms and the possible behavioral, social and environmental factors that may influence them. As part of this project, we are also completing an improved and more accurate Health Related Quality of Life measure which specifically takes into account the many non-motor symptoms and their effect on patients’ quality of life. In parallel, behavioral, electrophysiological, neuroanatomical, and molecular characterization of a number of genetic mouse models have provided us with a clearer picture of the specific cellular events that lead to dysfunction and ultimate degeneration of cells. The collective insights from all projects not only can provide us with potential novel therapeutic targets, but are also being actively used in the pre-clinical testing of a number of potential new drugs for PD.