Semaphorin 3A—Glycosaminoglycans Interaction as Therapeutic Target for Axonal Regeneration

Abstract

Semaphorin 3A (Sema3A) is a cell-secreted protein that participates in the axonal guidance pathways. Sema3A acts as a canonical repulsive axon guidance molecule, inhibiting CNS regenerative axonal growth and propagation. Therefore, interfering with Sema3A signaling is proposed as a therapeutic target for achieving functional recovery after CNS injuries. It has been shown that Sema3A adheres to the proteoglycan component of the extracellular matrix (ECM) and selectively binds to heparin and chondroitin sulfate-E (CS-E) glycosaminoglycans (GAGs). We hypothesize that the biologically relevant interaction between Sema3A and GAGs takes place at Sema3A C-terminal polybasic region (SCT). The aims of this study were to characterize the interaction of the whole Sema3A C-terminal polybasic region (Sema3A 725–771) with GAGs and to investigate the disruption of this interaction by small molecules. Recombinant Sema3A basic domain was produced and we used a combination of biophysical techniques (NMR, SPR, and heparin affinity chromatography) to gain insight into the interaction of the Sema3A C-terminal domain with GAGs. The results demonstrate that SCT is an intrinsically disordered region, which confirms that SCT binds to GAGs and helps to identify the specific residues involved in the interaction. NMR studies, supported by molecular dynamics simulations, show that a new peptoid molecule (CSIC02) may disrupt the interaction between SCT and heparin. Our structural study paves the way toward the design of new molecules targeting these protein–GAG interactions with potential therapeutic applications.

Self-supervised graph representation learning integrates multiple molecular networks and decodes gene-disease relationships

“… 76 Studies show that semaphorin-3a (Sema3a)-induced axonal growth cone collapse depends on HS3ST, indicating that activities of the semaphorin family rely on HS modifications. 77 , 78 , 79 TPGs of alopecia mainly cluster into two pathways termed the “Wnt signaling pathway” and the “Hippo signaling pathway” ( Figure 4 L). A previous study indicated that Wnt/β-catenin and Hippo signaling pathways played important roles in hair follicle regeneration 80 and development of alopecia.…”

Epigallocatechin-3-gallate alleviates gestational stress-induced postpartum anxiety and depression-like behaviors in mice by downregulating semaphorin3A and promoting GSK3β phosphorylation in the hippocampus

“…In the present study, we found that Sema3A expression in the hippocampus was increased in a mouse model of PPD, which was associated with anxiety and depression-like symptoms. As Sema3A is an axon guidance molecule ( Perez et al, 2021 ) and the accumulation of Sema3A in the hippocampus can induce programmed cell death of neurons ( Good et al, 2004 ), we speculate that the upregulation of hippocampal Sema3A in PPD mice influences synaptic plasticity or neuronal activity to cause anxiety and depression-like behaviors.…”

“…Semaphorin 3A (Sema3A) is a secreted protein in the nervous system that is involved in axon guidance ( Perez et al, 2021 ), neuronal migration ( Chen et al, 2008 ), and synapse formation ( Tillo et al, 2012 ). Sema3A has been implicated in neuropsychiatric diseases such as schizophrenia ( Gilabert-Juan et al, 2015 ), Alzheimer’s disease (AD; Wang et al, 2021 ) and epilepsy ( Van Battum et al, 2015 ), and its accumulation in hippocampal neurons induces programmed cell death, which is shown to contribute to AD development ( Good et al, 2004 ).…”