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.
Highlights
Parkinson's disease (PD) is a debilitating neurodegenerative disease, second in prevalence to Alzheimer's disease
The human PD-associated SNCA A30P point mutation was engineered into a human genomic DNA bacterial artificial chromosome (BAC) construct derived from clone PAC-27 M07 using positive/negative selection/counter-selection homologous recombination in E. coli as previously described (AlegreAbarrategui et al, 2009)
The inclusion of 18 kb of 5′ promoter ensures the presence of the NACP-Rep1 repeat element which lies approximately 10 kb upstream of the transcriptional start site, and is an important regulatory element (Jakes et al, 1994; Ueda et al, 1993)
Summary
Parkinson's disease (PD) is a debilitating neurodegenerative disease, second in prevalence to Alzheimer's disease. PD is primarily considered a dopaminergic disorder, characterized by motor phenotypes, including resting tremor, bradykinesia, rigidity and postural instability (Dauer and Przedborski, 2003; Olanow and Tatton, 1999). Post-mortem PD brain tissue shows loss of midbrain dopamine (DA) neurons and accumulation of Lewy bodies, protein aggregates largely composed of. Recent post-mortem neuropathological analysis of a PD patient with an A30P α-synuclein mutation showed strong neuropathological similarities between A30P and idiopathic PD patients (Seidel et al, 2010), confirming the relevance of the mutation to PD. The function(s) of α-synuclein, a 140 amino acid protein highly abundant in presynaptic terminals, are incompletely resolved. In PD, α-synuclein accumulation and Lewy body formation occur early in structures highly prone to neurodegeneration
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