Multiple system atrophy (MSA) is a progressive neurodegenerative condition that causes Parkinsonism, ataxia and autonomic failure. MSA is unresponsive to treatment and fatal within a decade of diagnosis. The pathology of MSA includes neuronal loss, astrogliosis and formation of glial cytoplasmic inclusions (GCI). GCIs are found predominantly within oligodendrocytes and contain fibrillar deposits of the neuronal presynaptic protein ?-synuclein. Evidence from in vitro experiments, autopsy studies and transgenic mouse models suggests that GCI formation is mechanistically involved in the neuronal degeneration of MSA. The long-term aim of this work is to understand how glial-neural interactions are involved in the pathogenesis of MSA, and to develop neuroprotective strategies that exploit the underlying molecular physiology. ? As a model organism, the zebrafish has many properties that may prove favorable for identifying factors that cause neurodegeneration as a consequence of oligodendroglial ?-synuclein expression and deposition. The zebrafish brain is rich in oligodendrocytes, retains the same basic organization of other vertebrate brains and has specialized neuronal populations of direct relevance to the study of MSA. Powerful genetic and in vivo drug screening techniques have been developed in the zebrafish, and these tools could be deployed in a zebrafish MSA model to identify genes and pharmaceutical compounds that modulate the expression of pathology. ? In this exploratory grant application, we propose to test the hypothesis that expression of human ?-synuclein in oligodendrocytes of the zebrafish brain will lead to the formation of glial cytoplasmic inclusions and progressive neuronal loss. In order to test this hypothesis, we will establish transgenic zebrafish lines from germline chimeras we have generated that express ?-synuclein under control of the zebrafish myelin P0 promoter (aim 1). We will analyse these transgenic fish in comparison with wild-type fish for evidence of formation of insoluble ? -synuclein deposits with histological and biochemical properties similar to glial cytoplasmic inclusions (aim 2), and degeneration of dopaminergic neurons or cerebellar Purkinje cells, or defects in myelination (aim 3). ? The data generated by these experiments will lend support to the central involvement of ectopic oligodendroglial expression of ?-synuclein and GCI formation in the pathogenesis of MSA. Furthermore, the resulting zebrafish model will be central to our future studies aimed at defining the molecular basis for oligodendrocyte-directed neurodegeneration in MSA, and may be further developed as a high-throughput in vivo assay to enable isolation of novel neuroprotective agents for treatment of MSA. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS058369-01A1
Application #
7379793
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Sieber, Beth-Anne
Project Start
2008-01-01
Project End
2009-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
1
Fiscal Year
2008
Total Cost
$162,422
Indirect Cost
Name
University of Pittsburgh
Department
Neurology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Bai, Qing; Parris, Ritika S; Burton, Edward A (2014) Different mechanisms regulate expression of zebrafish myelin protein zero (P0) in myelinating oligodendrocytes and its induction following axonal injury. J Biol Chem 289:24114-28
Zhou, Yangzhong; Cattley, Richard T; Cario, Clinton L et al. (2014) Quantification of larval zebrafish motor function in multiwell plates using open-source MATLAB applications. Nat Protoc 9:1533-48
Bai, Qing; Sun, Ming; Stolz, Donna B et al. (2011) Major isoform of zebrafish P0 is a 23.5 kDa myelin glycoprotein expressed in selected white matter tracts of the central nervous system. J Comp Neurol 519:1580-96
Farrell, Thomas C; Cario, Clinton L; Milanese, Chiara et al. (2011) Evaluation of spontaneous propulsive movement as a screening tool to detect rescue of Parkinsonism phenotypes in zebrafish models. Neurobiol Dis 44:9-18
Bai, Qing; Burton, Edward A (2011) Zebrafish models of Tauopathy. Biochim Biophys Acta 1812:353-63
Cario, Clinton L; Farrell, Thomas C; Milanese, Chiara et al. (2011) Automated measurement of zebrafish larval movement. J Physiol 589:3703-8
Burton, Edward A; Palladino, Michael J (2010) Of fish, flies, worms and men: powerful approaches to neuropsychiatric disease using genetic models. Neurobiol Dis 40:1-3