| First Author | Taylor TN | Year | 2014 |
| Journal | Neurobiol Dis | Volume | 62 |
| Pages | 193-207 | PubMed ID | 24121116 |
| Mgi Jnum | J:201961 | Mgi Id | MGI:5516368 |
| Doi | 10.1016/j.nbd.2013.10.005 | Citation | Taylor TN, et al. (2013) Region-specific deficits in dopamine, but not norepinephrine, signaling in a novel A30P alpha-synuclein BAC transgenic mouse. Neurobiol Dis 62C:193-207 |
| abstractText | 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 alpha-synuclein. Approximately 5-10% of PD patients have a familial form of Parkinsonism, including mutations in alpha-synuclein. To better understand the cell-type specific role of alpha-synuclein on DA neurotransmission, and the effects of the disease-associated A30P mutation, we generated and studied a novel transgenic model of PD. We expressed the A30P mutant form of human alpha-synuclein in a spatially-relevant manner from the 111kb 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 A30P alpha-synuclein or wildtype alpha-synuclein restored the sensitivity of DA neurons to MPTP in resistant Snca-/- animals. A30P 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-A30P Snca-/- mice but no changes to release of another catecholamine, norepinephrine (NE), in the NE-rich ventral bed nucleus of stria terminalis. SNCA-A30P Snca-/- mice had no overt behavioral impairments but exhibited a mild increase in wheel-running. In summary, this refined PD mouse model shows that A30P alpha-synuclein preferentially perturbs the dopaminergic system in the dorsal striatum, reflecting the region-specific change seen in PD. |
