Nigrostriatal overabundance of α-synuclein leads to decreased vesicle density and deficits in dopamine release that correlate with reduced motor activity

Abstract

α-Synuclein (α-syn) is a presynaptic protein present at most nerve terminals, but its function remains largely unknown. The familial forms of Parkinson's disease associated with multiplications of the α-syn gene locus indicate that overabundance of this protein might have a detrimental effect on dopaminergic transmission. To investigate this hypothesis, we use adeno-associated viral (AAV) vectors to overexpress human α-syn in the rat substantia nigra. Moderate overexpression of either wild-type (WT) or A30P α-syn differs in the motor phenotypes induced, with only the WT form generating hemiparkinsonian impairments. Wild-type α-syn causes a reduction of dopamine release in the striatum that exceeds the loss of dopaminergic neurons, axonal fibers, and the reduction in total dopamine. At the ultrastructural level, the reduced dopamine release corresponds to a decreased density of dopaminergic vesicles and synaptic contacts in striatal terminals. Interestingly, the membrane-binding-deficient A30P mutant does neither notably reduce dopamine release nor it cause ultrastructural changes in dopaminergic axons, showing that α-syn's membrane-binding properties are critically involved in the presynaptic defects. To further determine if the affinity of the protein for membranes determines the extent of motor defects, we compare three forms of α-syn in conditions leading to pronounced degeneration. While membrane-binding α-syns (wild-type and A53T) induce severe motor impairments, an N-terminal deleted form with attenuated affinity for membranes is inefficient in inducing motor defects. Overall, these results demonstrate that α-syn overabundance is detrimental to dopamine neurotransmission at early stages of the degeneration of nigrostriatal dopaminergic axons.

Remodeling of Lipid Vesicles into Cylindrical Micelles by α-Synuclein in an Extended α-Helical Conformation

“…Synapses of mice knocked out for ␣S showed diminished levels of synaptic vesicles in the reserve pool (2), whereas overexpression of ␣S is reported to inhibit re-clustering of synaptic vesicles, thereby reducing neurotransmitter release (15). These and other reports (21)(22)(23) suggest that ␣S interacts directly with membranes to control cycles of synaptic vesicle release.…”

Polo-like kinase 2 regulates selective autophagic α-synuclein clearance and suppresses its toxicity in vivo

“…Previous studies from our group and others have established that the decrease in TH + neuron number, induced by α-syn overexpression in this rat model, is due to neuronal loss rather than the loss of dopaminergic phenotype. In these studies, quantification of Nissl-positive or cresyl violet-positive cells in the SNc revealed a reduction of the number of positive cells, after α-syn overexpression, compared with the noninjected side, confirming that the neurons had indeed degenerated (25,27).…”

α-synuclein and synapsin III cooperatively regulate synaptic function in dopamine neurons

“…The decrease of dopamine overflow in these mice is not dependent on dopamine D2 autoreceptors misfunctioning or changes in dopamine re-uptake , thus indicating that other molecules, affected by the absence of α-syn, contribute to this phenomenon. Similar to the absence of α-syn, the increase of its protein levels in the nigrostriatal system causes a decrease of vesicle density and reduces dopamine release, thus promoting motor deficits (Garcia-Reitbock et al, 2010;Gaugler et al, 2012;Lundblad et al, 2012;Tofaris et al, 2006).…”