Thrombospondins (TSPs) are a family of oligomeric glycoproteins that interact with various components of the cell surface, extracellular matrix, growth factors, and proteases throughout the body, influencing a range of cellular interactions and processes such as angiogenesis, inflammation, osteogenesis, cell proliferation, and apoptosis. Recent studies have highlighted the significant role of TSPs in the development of the central nervous system (CNS), particularly in promoting synapse formation and regulating synaptic function, primarily through interactions with neuronal receptors.
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Structural Characteristics of TSPs
Synapses are the fundamental units of communication in the CNS, crucial for signal transmission between neurons. The formation and maintenance of synapses, which are essential for learning and memory, involve a complex interplay of numerous ligands and cell surface molecules. Astrocytes, a type of glial cell, secrete various molecules including TSPs, which play a critical role in regulating the formation and maintenance of synapses and dendritic spines.
TSPs are large, multi-domain proteins consisting of five members (TSP1-5), divided into two subgroups based on their oligomerization domains: trimeric subgroup A (TSP1 and TSP2) and pentameric subgroup B (TSP3, TSP4, and TSP5). Evolutionarily conserved, TSPs exhibit over 95% homology between mouse and human proteins. TSPs interact with various cell membrane receptors, extracellular matrix components, and cytokines to control and regulate cellular adhesion, migration, and morphological changes while inhibiting angiogenesis and tumor growth. The expression and function of TSPs vary across different tissues. For instance, TSP1 and TSP2 are associated with tissue injury and remodeling, promoting neuronal migration and axon outgrowth, while TSP3 and TSP5 are highly expressed in vascular walls and tendons. TSP4, along with TSP2, is crucial in regulating synapse formation and plasticity.
Fig. 1 The model for a "synaptogenic signaling complex" activated by TSP that potentially regulates prosynaptogenic-signaling pathways (Risher W.C., Eroglu C, 2012).
Mechanisms of TSP-Mediated Synapse Formation
Astrocyte-secreted TSPs are key regulators of synapse formation, structure, and function, capable of promoting synaptogenesis both in vivo and in vitro. TSPs achieve this primarily through their interactions with receptors such as α2δ-1 and neuroligins (NLs).
TSP-α2δ-1 Pathway
In 2005, Christopherson et al. demonstrated that immature astrocytes expressing TSP1 and TSP2 promote CNS synapse formation. However, the mechanisms by which TSPs induce new synapses were not fully understood until 2009 when Eroglu et al. found that TSPs (specifically TSP1, TSP2, and TSP4) interact with the voltage-gated calcium channel subunit α2δ-1. The drug gabapentin, which binds to α2δ-1, inhibits its interaction with TSPs, blocking TSP-induced synaptogenesis.
α2δ-1, initially identified as a non-essential subunit of skeletal muscle L-type calcium channels, is highly expressed in CNS neurons. Structurally, α2δ-1 is translated from a single gene product, which is cleaved into α2 and δ components that are linked by a disulfide bond. The α2 portion is entirely extracellular, while the δ portion contains a transmembrane domain and a short cytoplasmic tail, anchoring the protein to the membrane and facilitating its interaction with other proteins. During synapse formation, α2δ-1 serves as the extracellular ligand-binding part of the postsynaptic "synaptic signaling complex," promoting initial synaptic adhesion between dendrites and axons. TSPs bind to the von Willebrand factor domain of α2δ-1, causing structural rearrangements that trigger intracellular signaling, leading to the recruitment of synaptic adhesion molecules and ultimately, synapse formation.
Further research on the TSP-α2δ-1 signaling pathway has expanded our understanding of its role in synaptic regeneration and the enhancement of excitatory synaptic connectivity. Crawford et al. found that astrocyte-derived TSPs interact with α2δ-1 to influence synaptic plasticity without altering calcium channel function, suggesting other downstream effectors, such as enzymes, might play crucial roles. Faria et al. showed that overexpression of α2δ-1 in the cortex increased excitatory synaptic connectivity, indicating a direct correlation between α2δ-1 expression and cortical excitability. Risher et al. observed that intermittent alcohol exposure during adolescence caused dysregulation of astrocyte signaling molecules, leading to persistent hippocampal structural and functional abnormalities, highlighting the impact of TSP-α2δ-1 interactions on neuronal circuitry during development.
TSPs and Neuroligins
Neuroligins (NLs) are postsynaptic cell adhesion molecules that play significant roles in synapse formation and maturation. Comprising multiple domains, including a signal peptide, cholinesterase-like domain, carbohydrate-binding region, a transmembrane domain, and a short C-terminal tail, NLs mediate synaptic connections through their interactions with neurexins, a family of presynaptic adhesion molecules. Different NL subtypes are localized to specific synapses: NL1 is found in excitatory synapses, NL2 in inhibitory synapses, and NL3 in both types.
TSPs can regulate synaptogenesis through their interactions with NLs. Xu et al. found that TSP1 promotes synapse formation in developing neurons through NL1, with NL1 knockdown reducing TSP1-induced synaptogenesis. In Alzheimer's disease (AD), characterized by synaptic dysfunction, Kim et al. observed that human umbilical cord blood-derived MSCs secrete TSP1, which protects hippocampal synapses from amyloid-beta-induced damage through interactions with NL1 and α2δ-1 receptors.
NLs also play critical roles in synaptic maturation. Wittenmayer et al. demonstrated that NL1 knockout mice exhibit immature synaptic vesicle structures and functions, whereas overexpression of NL1 induces mature synaptic characteristics, underscoring NL1's involvement in synaptic assembly and maturation.
Interaction with Other Extracellular Matrix Proteins and Receptors
TSPs also interact with various extracellular matrix proteins and cell surface receptors, contributing to the regulation of synaptic structure and function. Microglia and astrocytes, through their secretion of cytokines like TNF-α, IL-1β, and IL-6, are involved in synapse formation and long-term potentiation. TSPs regulate the inflammatory response after CNS injury by interacting with receptors such as CD36 and CD47, enhancing the release of cytokines like IL-6, which are crucial for synaptic plasticity. TSP1 also interacts with TGF-β1, modulating synaptic formation at neuromuscular junctions and regulating MMPs during cortical injury, which is essential for synaptic network establishment and extracellular matrix remodeling.
Moreover, TSPs influence the actin cytoskeleton, a critical component for synaptic morphology. Actin cytoskeleton reorganization, controlled by Rho GTPases, is vital for dendritic spine formation and synaptic remodeling. TSP1 interacts with calreticulin and LRP-1, leading to RhoA inactivation and subsequent changes in the actin cytoskeleton, highlighting a potential pathway for TSP1 in regulating synaptic function.
TSPs, as oligomeric extracellular matrix proteins, play crucial roles in synapse formation and CNS repair post-injury, making them potential targets for treating CNS disorders like AD.
References
- Risher W.C., Eroglu C. Thrombospondins as key regulators of synaptogenesis in the central nervous system. Matrix Biology. 2012, 31 (3): 170-7.
- Lawler J. The functions of thrombospondin-1 and-2. Current Opinion in Cell Biology. 2000, 12 (5): 634-40.
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