Role of α-Synuclein in Presynaptic Dopamine Recruitment

Abstract

Real-time monitoring of stimulated dopamine release in mice with different ␣-synuclein expression was used to study the role of ␣-synuclein in presynaptic dopamine recruitment. Repeated electrical stimulations of ascending dopaminergic pathways decreased the capacity of the readily releasable pool (RRP) and temporarily increased its refilling rate, significantly slowing the rate of dopamine decline in mice with normally expressed ␣-synuclein. Mice with ␣-synuclein null mutation demonstrated a permanent increase of the refilling rate. This increase maintained stable dopamine release during stimulation (which induced dopamine decline in other animals) and served as an adaptation to altered dopamine compartmentalization. Mice without ␣-synuclein and with overexpression of human A30P mutated ␣-synuclein had a lower capacity of the dopamine storage pool than other animals. Reducing capacity of the storage pool in transgenic A30P mice led to paradoxical effects of L-dopa, which elevated dopamine release in response to single stimulation but decreased the refilling rate of the RRP.

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

“…What is happening upon a-synuclein knockout? Here studies report decreased exocytosis [33,35,37,38], no change [36,39], or even increased exocytosis [40][41][42] (Table 2). However, these studies need to be interpreted with care because a-synuclein is not the only synuclein isoform, and loss of physiological function could possibly be compensated by b-or g-synuclein.…”

RNA interference mediated silencing of α-synuclein in MN9D cells and its effects on cell viability

“…One theory suggested that -synuclein might be linked to PD via the regulation of dopamine (DA) homeostasis [19][20][21][22][23] . Several studies have proposed that -synuclein may be involved in regulating the biosynthesis, vesicles storage and release, as well as reuptake of DA [24][25][26][27][28][29][30][31] . In addition, -synuclein, as a chaperone, has been reported to interact with many other proteins, including 14-3-3, ERK1/2, parkin, etc.…”

Large α-synuclein oligomers inhibit neuronal SNARE-mediated vesicle docking

“…For example, overexpression of α-Syn resulted in reduction of dopamine release by interfering with a step after vesicle docking in exocytosis (27,28) or by inhibiting the reclustering of synaptic vesicles at the active zone after endocytosis (29). When the α-Syn level was reduced, the number of vesicles in the reserved pool decreased (30), but more vesicles were found in the readily releasable pool (31). In contrast, Südhof and coworkers (25) recently found that α-Syn promotes SNARE complex formation through its binding to a vesicular SNARE protein, synaptobrevin-2.…”