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 111 kb 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.

Synucleins Have Multiple Effects on Presynaptic Architecture

“…The loss-of-function is likely due to the fact that the PARK1/hA30P mutant does not fold completely in the presence of acidic lipids and targeted inefficiently to synapses. Functionally, the A30P mutant is associated with decreased neurotransmitter release only in some but not all types of dopaminergic synapses (Taylor et al, 2014), and not in hippocampal synapses (Nemani et al, 2010), quite different from the αβγ-Syn−/− synapses. These differences might be due to the increased connectivity of SVs in the intermediate zone of PARK1/hA30P and the decreased connectivity in αβγ-Syn−/− transgenic synapses (Fig.…”

Striatal dopamine neurotransmission: Regulation of release and uptake

“…Conversely, transgenic rodent lines overexpressing human wild-type alpha-synuclein, at levels that approximate those following gene locus multiplication in PD, show deficits in DA transmission in dorsal but not ventral striatum [198]. The A30P or A53T mutations appear to inhibit DA release consistent with gain-of-function mutations [192,193,199,200]. …”

Alpha-synuclein modulates dopamine neurotransmission

“…In a bacterial artificial chromosome (BAC) alpha-synuclein overexpressing mouse model generated by the Janezic‘s group, early stage decrease in dopamine release was measured via in vivo recording. The measured early stage attenuation of dopamine release in this animal model is attributed to decreased vesicle clustering that precedes the changes in the firing activity of dopamine neurons [61]. Importantly, these changes were only present in the nigrostriatal dopaminergic neurons [61].…”

“…The measured early stage attenuation of dopamine release in this animal model is attributed to decreased vesicle clustering that precedes the changes in the firing activity of dopamine neurons [61]. Importantly, these changes were only present in the nigrostriatal dopaminergic neurons [61]. Lam et al generated an overexpressing alpha-synuclein mouse model driven by the Thy1 promoter [50].…”