Journal
NEUROBIOLOGY OF DISEASE
Volume 62, Issue -, Pages 193-207Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2013.10.005
Keywords
Parkinson's disease; alpha-Synudein; Dopamine; Norepinephrine; Voltammetry; Behavior
Categories
Funding
- Parkinson's UK
- Monument Trust Discovery Award from Parkinson's UK
- Medical Research Council
- Wellcome Trust
- Neuroscience Scholars Program of the Society for Neuroscience
- Wellcome Trust Studentship in Neuroscience
- Wellcome Trust Core Award [090532/Z/09/Z]
- MRC [MC_UU_12021/2, MR/J004324/1, MC_U137761449] Funding Source: UKRI
- Alzheimers Research UK [ART-EG2007A-3] Funding Source: researchfish
- Medical Research Council [MR/J004324/1, MC_U137761449, MC_UU_12021/2] Funding Source: researchfish
- Parkinson's UK [G-0801, G-1003, G-0803, J-0901] Funding Source: researchfish
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Parkinson's disease (PD) is a neurodegenerative disorder classically characterized by the death of dopamine (DA) neurons in the substantia nigra pars compacta and by intracellular Lewy bodies composed largely of a-synuclein. Approximately 5-10% of PD patients have a familial form of Parkinsonism, including mutations in a-synuclein. To better understand the cell-type specific role of a-synudein on DA neurotransmission, and the effects of the disease-associated A3OP mutation, we generated and studied a novel transgenic model of PD. We expressed the A3OP mutant form of human a-synudein in a spatially-relevant manner from the 111 kb SNCA genomic DNA locus on a bacterial artificial chromosome (BAC) insert on a mouse null (Snca -/-) background. The BAC transgenic mice expressed alpha-synuclein in tyrosine hydroxylase-positive neurons and expression of either A3OP alpha-synuclein or wildtype alpha-synuclein restored the sensitivity of DA neurons to MPTP in resistant Snca-/- animals. A3OP alpha-synuclein mice showed no Lewy body-like aggregation, and did not lose catecholamine neurons in substantia nigra or locus coeruleus. However, using cyclic voltammetry at carbon-fiber microelectrodes we identified a deficit in evoked DA release in the caudate putamen, but not in the nucleus accumbens, of SNCA-A3OP Snca-/- mice but no changes to release of another catecholamine, norepinephrine (NE), in the NE-rich ventral bed nucleus of stria terminalis. SNCA-A3OP Snca-/- mice had no overt behavioral impairments but exhibited a mild increase in wheel-running. In summary, this refined PD mouse model shows that MOP asynuclein preferentially perturbs the dopaminergic system in the dorsal striatum, reflecting the region-specific change seen in PD. (C) 2013 The Authors. Published by Elsevier Inc. All rights reserved.
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