Figure 2. Impact of α-Syn and Tau on Ca... | Rockefeller University Press

Figure 2.

Impact of α-Syn and Tau on Ca2+homeostasis and synaptic transmission. (A) Physiological condition: Under healthy conditions, the SV pool is replenished with new vesicles through endocytosis. Newly endocytosed vesicles can either contribute directly to neurotransmitter release or be recycled via endosomes before exocytosis. α-Syn modulates both the endocytosis and exocytosis of SVs, while the native role of Tau at the presynapse remains poorly defined. Ca2+ release from presynaptic lysosomes, mitochondria, ER, and the extracellular environment is tightly regulated in response to an action potential arrival. (B) Pathological conditions: In disease states, Tau and α-Syn accumulate at presynaptic sites and interact with SVs. Tau binds to vesicles through the SV-associated protein Syngr3, while α-Syn interacts with SVs through a more complex mechanism. These interactions impair SV mobility and disrupt the vesicle cycle. Elevated levels of Tau and α-Syn may also increase interactions with mitochondrial, lysosomal, and ER membranes as well as associated Ca2+ transporters. This may lead to leaky lysosomal, mitochondrial and cellular membranes, dysfunctional Ca2+ transporters, and ER stress (denoted by lightning symbols), thereby disrupting Ca2+ and ATP homeostasis and exacerbating presynaptic toxicity. (C) Proposed model of SV mobility regulation by LLPS: Tau and α-Syn may influence the mobility of phase-separated SVs. Synapsin-mediated LLPS organizes the presynaptic SV pool by forming Synapsin-SV co-condensates (blue-shaded area). In vitro and in cell culture, α-Syn (pink) can infiltrate these condensates delaying the LLPS process. However, whether this affects SV mobility remains to be tested (indicated by “?”). Moreover, Tau (dark blue) is also present within the SV cluster and reduces SV mobility, but it is unclear whether LLPS mediates this effect (indicated by “?”). Collectively, we speculate that both α-Syn and Tau may play roles in regulating SV dynamics and mobility in vivo under both physiological and pathological conditions.

Impact of α-Syn and Tau on Ca ²⁺ homeostasis and synaptic transmission. (A) Physiological condition: Under healthy conditions, the SV pool is replenished with new vesicles through endocytosis. Newly endocytosed vesicles can either contribute directly to neurotransmitter release or be recycled via endosomes before exocytosis. α-Syn modulates both the endocytosis and exocytosis of SVs, while the native role of Tau at the presynapse remains poorly defined. Ca²⁺ release from presynaptic lysosomes, mitochondria, ER, and the extracellular environment is tightly regulated in response to an action potential arrival. (B) Pathological conditions: In disease states, Tau and α-Syn accumulate at presynaptic sites and interact with SVs. Tau binds to vesicles through the SV-associated protein Syngr3, while α-Syn interacts with SVs through a more complex mechanism. These interactions impair SV mobility and disrupt the vesicle cycle. Elevated levels of Tau and α-Syn may also increase interactions with mitochondrial, lysosomal, and ER membranes as well as associated Ca²⁺ transporters. This may lead to leaky lysosomal, mitochondrial and cellular membranes, dysfunctional Ca²⁺ transporters, and ER stress (denoted by lightning symbols), thereby disrupting Ca²⁺ and ATP homeostasis and exacerbating presynaptic toxicity. (C) Proposed model of SV mobility regulation by LLPS: Tau and α-Syn may influence the mobility of phase-separated SVs. Synapsin-mediated LLPS organizes the presynaptic SV pool by forming Synapsin-SV co-condensates (blue-shaded area). In vitro and in cell culture, α-Syn (pink) can infiltrate these condensates delaying the LLPS process. However, whether this affects SV mobility remains to be tested (indicated by “?”). Moreover, Tau (dark blue) is also present within the SV cluster and reduces SV mobility, but it is unclear whether LLPS mediates this effect (indicated by “?”). Collectively, we speculate that both α-Syn and Tau may play roles in regulating SV dynamics and mobility in vivo under both physiological and pathological conditions.

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