Molecular interaction of α-synuclein with p2x7 receptor

Alpha-synuclein (α-Syn) is a neuronal protein predominantly located at presynaptic terminals, where it interacts with synaptic vesicle membranes and facilitates neurotransmitter release under normal physiological conditions [18]. Its abnormal aggregation is a hallmark of synucleinopathies, such as Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy [23]. The purinergic receptor P2RX7, in contrast, is an ATP-gated transmembrane ion channel that becomes active during acute and chronic inflammatory states [12]. Activation of P2RX7 by ATP triggers pore formation, influx of multiple cations, and downstream effects ranging from cell proliferation to cytotoxicity. Prolonged activation can lead to receptor desensitization, excessive pore dilation, cell death, and amplified inflammation [6]. Recent studies suggest a functional interplay between α-Syn and P2RX7, which promotes mitochondrial impairment, elevated reactive oxygen species (ROS), oxidative stress, and neuroinflammation [26]. Computational analyses, including molecular docking and dynamics simulations, have identified the N-terminal region of α-Syn as a key mediator of its binding to P2RX7 [21]. Understanding this interaction sheds light on the mechanisms underlying synucleinopathies and highlights P2RX7 as a potential target for therapeutic interventions [14].