Increased Expression of α-Synuclein Reduces Neurotransmitter Release by Inhibiting Synaptic Vesicle Reclustering after Endocytosis

Abstract

Summary The protein α-synuclein accumulates in the brain of patients with sporadic Parkinson’s disease (PD), and increased gene dosage causes a severe, dominantly inherited form of PD, but we know little about the effects of synuclein that precede degeneration. α-Synuclein localizes to the nerve terminal, but the knockout has little if any effect on synaptic transmission. In contrast, we now find that the modest over-expression of α-synuclein, in the range predicted for gene multiplication and in the absence of overt toxicity, markedly inhibits neurotransmitter release. The mechanism, elucidated by direct imaging of the synaptic vesicle cycle, involves a specific reduction in size of the synaptic vesicle recycling pool. Ultrastructural analysis demonstrates reduced synaptic vesicle density at the active zone, and imaging further reveals a defect in the reclustering of synaptic vesicles after endocytosis. Increased levels of α-synuclein thus produce a specific, physiological defect in synaptic vesicle recycling that precedes detectable neuropathology.

α-Synuclein – Regulator of Exocytosis, Endocytosis, or Both?

“…Recent work in Parkinson's disease models with overexpression of wild-type a-synuclein show mainly an inhibitory effect of a-synuclein on neurotransmitter release [29][30][31][32][33][34], whereas two other studies come to the opposite conclusions [35,36]. In one of the latter increased synaptic activity was found in cultured hippocampal neurons acutely injected with a-synuclein.…”

“…Other effects have also been reported upon a-synuclein overexpression. One study found an increase in synaptic vesicle size, another a decrease of vesicle re-clustering after endocytosis, and two other studies report decreased motility of synaptic vesicles [29,32,46,47]. Interestingly, a-synuclein overexpression has also been shown to increase the amount of vesicles docked to the membranes [31], which would be in line with the recently Abbreviations and symbols: ", increase; #, decrease; À, no change; EM, electron microscopy; EPSC, excitatory postsynaptic current; FCV, fast-scan cyclic voltammetry; fEPSP, field excitatory postsynaptic potential; HPLC, high performance liquid chromatography; mEPSC, miniature EPSC; P, paired-pulse measurements; a-syn, a-synuclein.…”

The Theory of Brain Cell Activation

“…When suffer from AD, this function is impaired, intracellular calcium ion overload, causing the cells inside and outside calcium ions are relatively close to the static. TME can induce Ca 2+ inflowing, so will also be prompted Ca 2+ outflow rapidly of the Ca 2+ depot, because the stimulation is rhythmic, will cause Ca 2+ concentration of two-way oscillation [37].…”

“…This non-linear relationship makes synaptic vesicle fusion to be extremely sensitive changes for Ca 2+ concentration, and which is limited to a very narrow range of Ca 2+ concentration and a very short period. Regeneration of endogenous neurotransmitters including vesicle loading, transshipment and anchoring all need time and process [36,37]. In the process of rapid vesicle exocytosis, vesicles can release to rapid depletion.…”

Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson’s disease

“…Dopamine vesicle function is impaired in patients with PD, suggesting that dysfunctional dopamine handling is fundamental to the disease (14). Genetic mutations in several vesicular-associated proteins, such as α-synuclein, LRRK2 and synaptojanin, can lead to disrupted presynaptic dopamine handling and are commonly linked to PD (15)(16)(17)(18)(19)(20)(21)(22).…”