Region-specific deficits in dopamine, but not norepinephrine, signaling in a novel A30P α-synuclein BAC transgenic mouse.

Abstract

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 α-synuclein. Approximately 5-10% of PD patients have a familial form of Parkinsonism, including mutations in α-synuclein. To better understand the cell-type specific role of α-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 α-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 α-synuclein in tyrosine hydroxylase-positive neurons and expression of either A30P α-synuclein or wildtype α-synuclein restored the sensitivity of DA neurons to MPTP in resistant Snca-/- animals. A30P α-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 α-synuclein preferentially perturbs the dopaminergic system in the dorsal striatum, reflecting the region-specific change seen in PD.

• Authors: Tonya N Taylor, Dawid Potgieter, Sabina Anwar, Steven L Senior, Stephanie Janezic, Sarah Threlfell, Brent Ryan, Laura Parkkinen, Thierry Deltheil, Milena Cioroch, Achilleas Livieratos, Peter L Oliver, Katie A Jennings, Kay E Davies, Olaf Ansorge, David M Bannerman, Stephanie J Cragg, Richard Wade-Martins
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 62 Pg. 193-207 (Feb 2014) ISSN: 1095-953X [Electronic] United States
• PMID: 24121116 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013.

Chemical References

• alpha-Synuclein
• Dopamine
• Norepinephrine

Topics

• Age Factors
• Animals
• Basal Ganglia (metabolism)
• Chromosomes, Artificial, Bacterial
• Disease Models, Animal
• Dopamine (metabolism)
• Dopaminergic Neurons (metabolism)
• Female
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Norepinephrine (metabolism)
• Septal Nuclei (metabolism)
• alpha-Synuclein (genetics, metabolism)