Neuroscience 2005 Abstract
| Presentation Number: | 85.13 |
|---|---|
| Abstract Title: | Nigrostriatal dysfunction in transgenic mice overexpressing α-synuclein. |
| Authors: |
Fernagut, P. O.*1
; Hutson, C. B.1
; Fleming, S. M.1
; Rockenstien, E.
; Masliah, E.
; Levine, M. S.2
; Chesselet, M. F.1
1Neurology and Neurobiology, UCLA, Los Angeles, CA 2Mental Retardation Research Center, UCLA, Los Angeles, CA |
| Primary Theme and Topics |
Disorders of the Nervous System - Neurodegenerative and Movement Disorders -- Parkinson's disease: Models |
| Session: |
85. Synucleins I Poster |
| Presentation Time: | Saturday, November 12, 2005 1:00 PM-2:00 PM |
| Location: | Washington Convention Center - Hall A-C, Board # NN12 |
| Keywords: | PARKINSON, BASAL GANGLIA, MOUSE, ANIMAL MODEL |
Accumulation of alpha-synuclein is the pathological hallmark of several movement disorders including Parkinson’s disease (PD), dementia with Lewy bodies and multiple system atrophy. PD is characterized clinically by motor impairment (akinesia, bradykinesia, rigidity, postural instability) and pathologically by the widespread occurrence of alpha-synuclein positive inclusions (Lewy bodies) and neurodegeneration in selected brain regions including the substantia nigra (SN) and locus coeruleus (LC). Mice overexpressing human wild-type alpha-synuclein (Thy-1 promoter) display early and progressive sensorimotor impairments (Fleming et al., 2004) and deficits in olfaction and anxiety tests (Fleming et al. SFN abst. ’05). We have assessed the effects of alpha-synuclein overexpression (Rockenstein et al., 2002) on nigrostriatal function with radioligand binding for dopamine transporter (DAT: GBR-12395, 1, 2, 5, 10, 15, 20 nM) and vesicular monoamine transporter 2 (VMAT-2: dihydroterabenazine, 1, 2, 5, 10, 15, 20 nM). Alpha-synuclein overexpressing mice (ASO, 8 months old) displayed significantly reduced binding for DAT (-12.5%, p<0.05) and VMAT (-10.8%, p<0.0001). D2-type receptor binding (raclopride, 4nM) in the striatum and glutamic acid decarboxylase (GAD67) mRNA expression in the globus pallidus were similar between wild-type and ASO. Administration of paraquat to both wild-type and ASO mice induced a significant loss of tyrosine hydroxylase neurons in the ventral SN pars compacta most vulnerable to PD and in the LC. In ASO, paraquat also induced a marked increase in proteinase-K resistant alpha-synuclein inclusions. This mouse model is useful to study early stages of dopaminergic dysfunction that may occur prior to neurodegeneration in PD. The data show that paraquat, a pesticide that may increase the risk of PD, targets brain regions vulnerable in PD and promotes alpha-synuclein insolubility.
Supported by P50NS38367, U54ES12078
Sample Citation:
[Authors]. [Abstract Title]. Program No. XXX.XX. 2005 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience, 2005. Online.
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