The article "Keeping Neuronal Activity in Check: A Novel Role for α-Synuclein Serine-129 Phosphorylation in the Healthy Brain" by Danielle E. Mor explores the functional significance of the phosphorylation of the protein α-synuclein at serine-129 (Ser129P) within the healthy brain. Traditionally, Ser129P has been viewed as a marker of pathological aggregation in neurodegenerative diseases, such as Parkinson's disease and dementia with Lewy bodies. However, recent work by Parra-Rivas, Madhivanan et al. reveals that Ser129P plays an essential role in α-synuclein's physiological function, challenging the assumption that it is solely associated with disease states. This finding highlights a dual role for α-synuclein, where Ser129P acts as a regulatory mechanism that modulates normal synaptic function, specifically through its impact on neurotransmitter release and synaptic vesicle dynamics.
In their study, Parra-Rivas and colleagues used advanced optical assays to demonstrate that phosphorylation at Ser129 directly influences α-synuclein's ability to regulate synaptic vesicle recycling. They found that when α-synuclein is phosphorylated at Ser129, it clusters synaptic vesicles and reduces their recycling, which, in turn, decreases neurotransmitter release. By mutating serine-129 to either mimic or prevent phosphorylation, the researchers observed that phosphorylation enhances vesicle clustering, whereas its absence increases vesicle mobility. This suggests that α-synuclein, when phosphorylated at Ser129, plays a crucial role in maintaining synaptic homeostasis, potentially by restraining excessive neurotransmission following high neuronal activity.
The study further elucidates that Ser129P facilitates protein-protein interactions between α-synuclein and synaptic proteins, such as VAMP2 and synapsin. These interactions are strengthened in the presence of Ser129 phosphorylation and are instrumental in the protein's ability to bind to vesicles and regulate their clustering. Through both in vitro assays and in vivo models, the researchers confirmed that neuronal stimulation increases Ser129P, positioning it as a response to heightened synaptic activity. This phosphorylation-induced binding could thus represent a broader, activity-dependent homeostatic mechanism where α-synuclein moderates synaptic activity to prevent overexcitation.
The implications of these findings are significant as they challenge the conventional view of Ser129P as merely a pathological marker and open up new avenues for understanding its physiological roles. This work also raises questions about how the physiological phosphorylation of Ser129 might transition into a pathological state. Future research will be needed to further explore this transition and to determine if targeting Ser129P could provide novel therapeutic approaches for synucleinopathies.
