The role of snapin in regulation of brain homeostasis

Jiawen Li, Xinqi Huang, Yumei An, Xueshi Chen, Yiyang Chen, Mingyuan Xu, Haiyan Shan, Mingyang Zhang1,,*

Abstract Brain homeostasis refers to the normal working state of the brain in a certain period, which is important for overall health and normal life activities.Currently, there is a lack of effective treatment methods for the adverse consequences caused by brain homeostasis imbalance.Snapin is a protein that assists in the formation of neuronal synapses and plays a crucial role in the normal growth and development of synapses.Recently, many researchers have reported the association between snapin and neurologic and psychiatric disorders, demonstrating that snapin can improve brain homeostasis.Clinical manifestations of brain disease often involve imbalances in brain homeostasis and may lead to neurological and behavioral sequelae.This article aims to explore the role of snapin in restoring brain homeostasis after injury or diseases, highlighting its significance in maintaining brain homeostasis and treating brain diseases.Additionally, it comprehensively discusses the implications of snapin in other extracerebral diseases such as diabetes and viral infections, with the objective of determining the clinical potential of snapin in maintaining brain homeostasis.

Key Words: brain homeostasis; diabetes; neurological diseases; snapin; traumatic brain injury; vesicle fusion

Introduction

Brain homeostasis refers to the stable state of various physiological processes in the brain, including electrochemical balance, neurotransmitter regulation,and immune regulation (Muhie et al., 2023; Chen et al., 2024).When brain homeostasis is disrupted, it can lead to cognitive impairments, emotional changes, and autonomic nervous system dysfunction.Given that the etiology of disrupted brain homeostasis is yet unknown, temporary relief of symptoms can be achieved by using supportive therapy.However, treating disorders of brain balance remains a challenge.Recent studies have shown that Snapin(SNAP25-interacting protein), a type of protein, can help maintain brain homeostasis in synaptic transmission, neural development and maintenance,neural protection, and learning and memory, thereby offering potential research value in the prevention and treatment of brain disorders (Tammineni and Cai, 2017; Andres-Alonso et al., 2021).

Snapin was originally discovered in nerve cells as a receptor protein for SNAP-25 in the SNARE (soluble N-ethyl-maleamide-sensitive factor-binding protein receptor) complex and Snapin was enriched in neurons and exclusively located on synaptic vesicle membranes.Its relative molecular weight is about 15 kDa and consists of 136 amino acids.Its secondary structure is mainly composed of an α helix, wherein the N-terminal has a transmembrane hydrophobic region (1–20 aa), the C-terminal has a coiled-coil formed by two spiral regions of H1 and H2, and the spiral domain is conserved in many vesicle fusion proteins (Jeong et al., 2021).Snapin is involved in the composition of several complexes (BLOC-1 and BORC; Pu et al., 2015) and promotes the binding of Ca2+receptor proteins to the SNARE complex, not only to maintain the stability of the intracellular environment of nerve cells and communicate between cells but also to bind a series of proteins through the coiled-coil domain to assist neurotransmitter transport (Lee et al., 2022), neuronal elongation and development, and autophagy (Yuzaki, 2010).It has been reported that the Snapin-deficient mouse brain recapitulates AD-associated autophagic stress in axons, and overexpressing snapin reversed axonal autophagic stress in AD brains and built a foundation for developing potential AD therapeutic strategies (Tammineni and Cai, 2017; Tammineni et al., 2017).Hu et al.(2021) reported that snapin expression levels are associated with vesicle priming and synaptic homeostasis under high-frequency stimulation,potentially causing cognitive impairment in schizophrenia.Recent studies have also revealed a role in the regulation of insulin secretion, making snapin a possible drug target for diabetes (Shen et al., 2011; Somanath et al., 2016;Jiang et al., 2021).Jiang et al.(2021) reported that snapin mediates β cells’proliferation and insulin secretion and may likely be a pharmacotherapeutic target for diabetes mellitus.

These results suggest that snapin plays an important role in steady-state regulation and can be used as a therapeutic target in brain disease.Therefore,this review attempts to summarize the detailed role of snapin in the regulation of brain homeostasis and rationalize the basic understanding of the role of snapin in the treatment for brain disease.

Retrieval Strategy

A computer-based online search of the PubMed database was performed to retrieve articles published up to August 31, 2023.A combination of the following text words (MeSH terms) was used to maximize search specificity and sensitivity: “brain homeostasis,” “snapin protein,” “TBI,” “synapse,”“vesicle fusion,” “Cypin,” “SPAG6,” “Dynein,” “AC6,” “autophagy-lysosome system,” “neuronal growth and development,” “autophagy-lysosome system,”and “diabetes.” The results were further screened by title and abstract,and only studies exploring the relationship among snapin, the brain, and extracerebral homeostasis were included to investigate the therapeutic perspective of snapin for neuronal diseases and some extracerebral disorders.No language or study type restrictions were applied.

The Role of Snapin in the Regulation of the Nervous System Function

Homeostasis in the brain includes neuronal activity, synaptic transmission,and stability of neural circuits.Snapin plays an important role in the regulation of nervous system function and neural growth and development.Snapin is also a protein involved in synaptic vesicle transport and aggregation, which affects the volume and efficiency of neurotransmitter release, neuronal cell differentiation, and synapse formation.In addition, snapin plays an important role in maintaining cellular health and homeostasis in neurons by regulating the autophagic lysosomal system (Zhou et al., 2012; Tammineni and Cai,2017).All these functions emphasize the importance of snapin for brain homeostasis.

Role of Snapin in neuronal transmitter release Snapin regulates Ca2+ to affect vesicle fusion

Synaptic homeostasis mechanisms are particularly sensitive to snapin levels (Dickman et al., 2012).When a nerve signal reaches the presynaptic membrane, neurotransmitters are stored in synaptic vesicles, awaiting fusion with the synapse membrane.If vesicle fusion is disrupted, such as when the fusion process is blocked or when there is insufficient neurotransmitter release, neurotransmission is dysfunctional.

It is known that presynaptic action potentials (APs) activate voltage-gated calcium channels, allowing calcium to enter and then interact with synaptic receptors (synaptic-binding proteins) to trigger rapid vesicle fusion and trigger neurotransmitter release.Since synaptic vesicle fusion is Ca2+dependent,snapin enhances the activity of the Cav1.3L channel variant equipped with a long carboxyl terminus, which is important for the vesicle fusion process.This action does not change other biophysical properties, including voltagedependent gating characteristics, galvanic dynamics, and calcium-dependent inactivation.Experiments have shown that snapin increases the opening probability of Cav1.3L channels without changing the surface expression level(Jeong et al., 2021) and the synaptic vesicle (SV) release probability (Pr),which determines the homeostatic and plastic control of neurotransmitter release (Ivanova et al., 2021).Snapin has also been shown to affect the synchronization of the synaptic vesicle fusion , which further illustrates that the enhancement of Cav1.3 activity in the presence of snapin can promote the precision and efficacy of synaptic transmission and hormone secretion (Jeong et al., 2021).

Snapin regulates the SNARE complex to the steps between transmitter release

Snapin regulation of the SNARE complex helps to achieve precise implementation of neurotransmitter release and synaptic function in brain homeostasis.The SNARE complex is a core protein that mediates vesicle fusion in neuronal synapses and is involved in neuronal extension, including the synaptic vesicle membrane protein VAMP/synaptobrevin, syntaxin, and SNAP-25 (Wang and Ma, 2022).SNAP-25 participates in the formation of the trans-SNARE complex in neuronal tissue and enhances its assembly (Kishimoto et al., 2019).By binding to the SNAP-25 protein, snapin facilitates stable binding of the SNARE complex to the Ca2+-sensitive protein synaptotagmin-1(Rizo, 2022), which reduces adverse reactions and regulates the motor process of vesicle production to anchoring.

Meanwhile, in the neurotransmitter-releasing apparatus, protein kinase A can regulate neurotransmitter release by directly acting on the relevant proteins (Overhoffet al., 2022).As an early discovered substrate for protein kinase A, snapin’s phosphorylation regulates synaptic transmission through a cAMP-dependent signal transduction cascade.Its phosphorylation leads to increased binding of synaptotagmin to the SNARE complex.Synaptotagmin is a Ca2+sensor that directs Ca2+into nerve endings after a wave of fast and synchronized vesicle fusion (Chapman, 2018), which accelerates the replenishment and fusion of vesicles (Polishchuk et al., 2023).Together with SNARE, it determines the procedure between transmitter releases.Thus,snapin plays a role in the plasticity of transmitter release (Cheng et al., 2018).

Snapin regulates the size of the SV pool to influence the intensity of transmitter release

As mentioned above, Ca2+is important in vesicle fusion and neurotransmitter release.Initiating synaptic vesicles to implement Ca2+-dependent fusion,SNARE membrane fusion machinery equipped with regulatory proteins and synaptotagmin are required (Rizo, 2022).Thus, in addition to the sensitivity of Ca2+, proper regulation of SV pool size is essential to maintain synaptic activity and synchronized neurotransmitter release (Di Giovanni and Sheng, 2015).

It was found that the reduction of snapin in the hippocampus coincided with a large increase in presynaptic vesicles (Wang et al., 2023).The mechanism may be that snapin links the microtubule-based motor dynein with late endosomes (LEs) to regulate the retrograde transport of LEs (Xiang and Qiu,2020).At the same time, snapin, as a BLOC-1 subunit, influences BLOC-1-dependent endosome sorting (Bowman et al., 2021).Therefore, when snapin expression is enhanced, the transport of the SV inward lysosomal pathway is also enhanced, and the SV pool is reduced.

Thus, snapin affects the number of vesicle releases by regulating early endosomal sorting processes, thereby ensuring appropriate synaptic transmission strength and persistence to maintain a balanced state of brain homeostasis.

Snapin is involved in the growth and development of neurons

Snapin’s interaction with cypin

Microtubule assembly and disassembly can affect synaptogenesis and axonal transport of neurons in the brain (Barman et al., 2019), and snapin regulates neuronal growth and development through cypin thereby maintaining homeostasis in the brain.Cypin is a new target for the treatment of traumatic brain injury (TBI)(Swiatkowski et al., 2018).It is a protein that regulates the number of neural dendrites (Rodriguez et al., 2018), which binds to microtubule proteins through the collapsin response mediator protein (CRMP) homologous domain to promote microtubule assembly and dendrite formation (Sweet et al., 2022).Studies identified that snapin’s carboxyl-terminal curling helix domain (H2)binds to cypin’s CRMP homologous domain, which is also where tubulin binds(Swiatkowski et al., 2018).Thus, Snapin is more likely to occupy the binding site of Cypin than tubulin, which ultimately leads to reduced microtubule assembly, affecting the number of dendrites in neurons, manifested in altered neuronal dendrite patterns (Figure 1).

Figure 1 ｜ Mechanisms of growth of neuronal synapses and operation of the autophagy-lysosomal system.

Snapin’s interaction with SPAG6

SPAG6 controls neuronal migration as well as neurological synapses and elongations (Yan et al., 2015).The interaction of snapin with amino acids 199–280 in the SPAG6 structural domain (Yuan et al., 2020) mediates the indirect regulation of neuronal growth and development.The Spag6 mutation causes vestibular dysfunction in mice (Li et al., 2021).The vestibular system is closely related to the neuronal network of the brain, and it performs homeostatic functions by transmitting information via synapses.Vestibular dysfunction results in the malfunctioning of signaling that negatively affects brain homeostasis.However, the mechanism of how snapin regulates SPAG has not yet been elucidated.

Snapin’s interaction with dynein

Brain-derived neurotrophic factor (BDNF) is the most abundant and widely distributed neurotrophic factor in the brain (Tsai, 2018; Camuso and Canterini,2023; Nguyen et al., 2023), and its Val66Met polymorphism has a positive role in the development and maintenance of brain homeostasis (Rezaei et al., 2022).Snapin, as a dynein adapter, recruits dynein motors to BDNFTrkB signaling endosomes, assisting with terminal BDNF-induced retrograde signaling.Such an action is crucial for the dendritic growth of cortical neurons(Zhou et al., 2012).At the same time, studies also show that BDNF Val(66)Met polymorphisms have a protective effect after TBI (Gustafsson et al., 2021).This provides possible molecular mechanisms for neuronal growth after TBI from the perspective of snapin (Figure 1).

Snapin’s interaction with AC6

Adenosine 3′,5′-cyclic mononucleotide (cAMP) is one of the most significant second messengers that control cellular signal transductions (Gopalakrishna et al., 2023).AC6 is the key enzyme that catalyzes cAMP synthesis.The study found that the N-terminus of AC6 can interact directly with Snapin to regulate synaptic growth (Beazely and Watts, 2006).There are two possible mechanisms for Snapin to regulate synaptic growth: regulating cAMP synthesis in the brain and altering the structure and localization of the SNARE complex (Wang et al., 2009; Figure 1).

Snapin is involved in the regulation of autophagy-lysosome system function in neurons

Snapin participates in localization and membrane fusion during autophagyAutophagy is a multifunctional degradation system that maintains cellular homeostasis (Nakatogawa, 2020).Macro-autophagy is a type of autophagy(Abdrakhmanov et al., 2020) that involves the formation of autophagosomes,which use double-membrane vesicles to sequester materials that will be sent to lysosomes for breakdown.The newly formed autophagosomes fuse with vesicles from the endolysosomal compartment, including early/late endosomes and lysosomes.This fusion process requires Snapin to modulate the synergy of SNARE and other regulators of membrane dynamics, just as vesicle fusion during neurotransmitter release (Zhao et al., 2021).Autophagy dysfunction leads to neuronal degeneration and disrupts nerve cell homeostasis (He et al., 2016).

Snapin acts as one subunit of the two cytosolic protein complexes BLOC-1 and BORC, and together with them completes membrane communication and organelle localization (Niwa et al., 2017).Snapin in BLOC-1 realizes early/recycling endosome membrane protein sorting and tabulation, and snapin in BORC realizes lysosomal localization in mammalian cells (Pu et al., 2015;Hartwig et al., 2018; Figure 1).

In addition, studies have shown that the process of late endocytic consignments’ delivery to the soma must be via the ligation of snapin and dynein (retrograde transport in motor neurons) to couple late endosomes,where late endosomes and lysosomes come into sufficient proximity for highefficient membrane fusion by motor-driven forces (Lu et al., 2009; Cai and Sheng, 2011).

Snapin-mediated retrograde transport avoids apoptosis of nerve cells

We know that the autophagy-lysosomal system is the primary degradation pathway necessary for neuronal maintenance and survival (Stavoe and Holzbaur, 2019).The mentioned snapin-dynein-mediated late endosomal lysosomal transport is involved in heterogeneous phagocytosis and autophagy of neurons, resulting in snapin playing a key role in the signaling pathways and normal retrograde transport of key neurons (Yuzaki, 2010; Shi et al., 2017),which guarantee efficient autophagy-lysosomal degradation to regulate synaptic plasticity and cell survival.

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Regarding retrograde transport, the study found that both substances phosphorylated snapin and adjusted retrograde transport.The first is DYRK3,which directly phosphorylates snapin at threonine (Thr) 14 residue and increases snapin with other proteins such as dynein and synaptotagmin-1,thereby increasing axonal retrograde transport (Lee et al., 2022).The second is p38α-MAPK.Although p38α-MAPK inhibits retrograde transport of substances like BACE1 in the axon, it phosphorylates snapin.Meanwhile,phosphorylated snapin inhibits p38α-MAPK, which created a feedback loop between p38α-MAPK and snapin (Schn?der et al., 2021; Figure 1).Snapin(–/–) neurons show damaged retrograde transport and assembly of late endosomes along the neurite, deviant accrual of immature lysosomes,and impaired removal of autolysosomes.Reintroducing the snapin transgene rescues these phenotypes (Cai and Sheng, 2011).Taken together, snapin circumvents neuronal apoptosis through this action, while maintaining neuronal viability.

The Role of Snapin in the Treatment for Brain Disease

There is an increased association between severe brain injury and neurodegenerative diseases such as Parkinson’s disease (Brettet al., 2022).Considering the importance of snapin in maintaining brain homeostasis, we investigated the use of snapin to treat the sequelae of brain disease.However,since relevant studies are still relatively limited, we focused on its mechanism of action in Alzheimer’s disease (AD) and schizophrenia.

Snapin and AD

TBI is the predominant non-genetic, non-age-related risk factor for AD (Shin et al., 2021).Amyloid-β (Aβ) peptides are produced by cleavage of amyloid precursor proteins (APP) by β and γ secretases (Cheignon et al., 2018).BACE1 is the main β secretase.If it is not cleaned up by retrograde transport in a timely manner, it will cause an abnormal accumulation of Aβ in the brain,seen as amyloid deposition and senile plaques.Accumulation of Aβ is the main cause of synaptic dysfunction and memory loss in people with AD (Tiwari et al., 2019; Pelucchi et al., 2022).

As mentioned above, the serine residue 112 on snapin is phosphorylated by p38α-MAPK phosphorylation (Schn?der et al., 2021), which then promotes the retrograde transport of BACE1 (Ye et al., 2017; Schn?der et al., 2021).Later, it was experimentally shown that flawed retrograde transport impaired autophagic clearance of AD neurons (Han et al., 2021).AD neurons mainly show defective retrograde transport at the axon and anterior ends of synapses.Aβ oligomers are enriched in axons and interact with dyskinin motors, interfering with the coupling of the dynein motor with its adaptor snapin, whereby they are trapped in distal axons and their degradation in somatic cells is disrupted (Tammineni and Cai, 2017).Recent research also confirms that snapin-enhanced retrograde transport reduces synaptic mitochondrial autophagy stress and improves mitochondrial defects and synaptic loss, thereby counteracting synaptic damage in the brains of AD mice(Han et al., 2020a, b).

Snapin and schizophrenia

Genetic studies have shown that schizophrenia involves different genetic loci, where the dysbindin gene (DTNBP1) at chromosome 6p24-22 is a susceptibility gene to human schizophrenia (Mohammadi et al., 2018;Suh et al., 2021; Jun et al., 2022).Studies have shown that snapin works synergistically with dysbindin andSNAP25during the regulation of synaptic homeostasis (Dickman et al., 2012; Wentzel et al., 2018).

A decrease in the snapin protein may be associated with schizophrenia.WhenDTNBP1(dystrobrevin-binding protein 1) in the sandy rat cannot be expressed, this phenomenon leads to social decline and cognitive impairment.It was confirmed that a 30-residue peptide in dysbindin (90–119 amino acids)mediated interaction with snapin, and the loss of dysbindin protein led to less snapin protein in the hippocampal structural region of the sandy mouse.The stability of snapin can eventually lead to neurological and behavioral abnormalities (Feng et al., 2008).These results indicate that the reduction of snapin is related to schizophrenia, and the underlying mechanism may be that the dysbindin protein promotes the release of neurotransmitters by upregulating the expression of the snapin protein.According to genetic evidence, snapin works synergistically with dysbindin to regulate the release of vesicles and possible steady-state plasticity (Dickman et al., 2012).Comprehensive characterization of Roman high (RHA-I) and low (RLA-I)avoidant rat strains, which are innate neurobehavioral models, by real-time qPCR and western blotting have confirmed elevated mRNA levels of Snap25,synaptophysin (Syp) in rhha-I’s PFC, and decreased expression of Vamp1 and snapin in HIP (Elfving et al., 2019).A more recent study used the calyx of Held synapses to record electrophysiology, dysbindin loss accompanied by a slight decrease in Munc18-1, and snapin expression levels.It follows that the direct interaction of dysbindin with Munc18-1 and snapin mediates calciumdependent readily releasable pool supplementation.During periods of highfrequency stimulation, a decrease in snapin can lead to cognitive impairment in schizophrenia (Hu et al., 2021).

Therapeutic role of snapin in other brain-related disorders

Snapin has been shown to be a key player in regulating synaptic mitochondrial homeostasis (Han et al., 2020b).Xie et al.(2015) demonstrated that snapin can reverse transport defects by working with hSOD1 (G93A), thereby salvaging autophagy-lysosomal defects, enhancing mitochondrial renewal,and improving the survival rate of amyotrophic lateral sclerosis (ALS) motor neurons.Because the interaction of the snapin and SNARE complexes participates in synaptic transmission and the maintenance of synaptic homeostasis, it has been considered a potential drug target for the treatment of autism (Gowthaman et al., 2006).Traumatic brain injury is a biochemical cascade of mechanical damage of the brain tissue and the neuronal cellular response elicited by external forces (Li et al., 2018; Xie et al., 2019), which can disrupt the stability of brain homeostasis and impair brain structure and function.In the case of TBI, the role of snapin in maintaining brain homeostasis in patients is critical, as snapin can help restore electrochemical homeostasis, neurotransmitter imbalances, and inflammatory responses caused by injury.Our group has focused the role of snapin in TBI, and preliminary results indicate that snapin is involved in the pathophysiological mechanisms after TBI (data not shown).

Snapin’s Role in Other Diseases

We further explore the importance of snapin in extracerebral diseases and broaden the understanding of snapin’s systemic function.

The extracerebral role of snapin on homeostasis regulation

In addition to promoting microtubule assembly by modulating cyclin, snapin also facilitates islet β-cell growth through this pathway.Snapin is irregularly and specifically expressed in the endocrine fraction of the islet, and proteins that interact with snapin are enriched in cell cycle regulation.After snapin knockdown, the β-cell cycle is stuck in the S phase, wherein cell proliferation is inhibited, and the expression of related binding proteins, CDK2, CDK4,and CCND1 proteins decreases at this stage (Jiang et al., 2021).At the sametime, fluorescent staining of snapin and insulin show that it binds to and cosecretes insulin, a process that relies on the Munc18/SNARE complex (Südhof and Rothman, 2009; Somanath et al., 2016).Snapin also binds directly to collectrin, a new target of HNF-1 in pancreatic β-cells that indirectly controls insulin activity.Therefore, snapin is also associated with insulin exocytosis(Fukui et al., 2005).

Meanwhile, studies have demonstrated that elevated levels of SNARE protein in human islet β cells can prevent pro-inflammatory cytokine-induced apoptosis (Aslamy et al., 2018; Oh et al., 2018).

The role of snapin with other downstream proteins/genes

Snapin binds to a variety of proteins to play a role in other areas, such as Exocyst, EBAG9, ACVI, the regulator of G protein signature 7 (RGS7), and members of the SNAP family (Table 1 and Figure 2).

Therapeutic role of snapin in extracerebral disorders

Snapin and diabetes

From the perspective of the effect of snapin on the cell cycle and by comparing it with lentiviral transfection of Min6 cells, it can be concluded that the expression of snapin promotes insulin secretion.However, the decrease in snapin expression inhibits β-cells, while increasing its expression inducesapoptosis and inhibits insulin protein/mRNA levels.Furthermore, hepatocyte nuclear factor HNF-1α mutations in pancreatic β-cell are strongly associated with juvenile mature pathogenic diabetes mellitus (MODY) (Song et al., 2011;Jiang et al., 2021).Yamagata et al.(2007) found that collectrin is HNF-1α’s new target, binding to SNAPIN to promote the SNARE complex formation.Other studies have found that the interactions between the C-terminal H2 region of snapin and the SN-1 region of Snap-25 control insulin exocytosis (Yu et al., 2013; Somanath et al., 2016; Gaisano, 2017).

Table 1 ｜Summary of snapin’s peripheral physiological effects

Figure 2 ｜Schematic of snapin’s interaction with a variety of proteins.

In addition to the indirect effects of snapin, protein kinase A-dependent phosphorylation also increases the interaction between insulin-secreted vesicle-related proteins, thereby enhancing glucose-stimulated insulin secretion.In diseased pancreatic islet β-cells, snapin can restore glucosestimulated insulin secretion by expressing a snapin mutant that mimics sitespecific phosphorylation (Song et al., 2011).From this, we believe that snapin improves the function of β-cell in type 2 diabetes mellitus.

Overall, both the direct and indirect effects of snapin on β-cells suggest that its therapeutic significance for diabetes can be further explored in future studies.

Snapin’s dual therapeutic significance for virus infection

Hicks et al.(2018) used a Y2H screen to discover that porcine reproductive and respiratory syndrome virus can specifically interact with snapin in the host cell, and play a role in intracellular transport and membrane fusion.It is suggested that the upregulation or downregulation of snapin can be used to control virus infection.

One study found that the snapin protein can downregulate the replication of human cytomegalovirus associated with neonatal mental retardation(Shen et al., 2011).The replication and growth of human cytomegalovirus in human cells require viral proteins such as primer enzyme UL70 (Shen et al.,2011), helicase UL105 (Luo et al., 2013) that encodes the DNA replication mechanism, and UL128/130/131 (Wang et al., 2016) that acts specifically with snapin.These viral proteins’ expression increases in anti-snapin siRNA-treated cells.

Human immunodeficiency virus 1 (HIV-1) escapes detection in dendritic cell (DC) during viral uptake, intracellular trafficking and in the cytosol by the pattern-recognition receptor (PRR), such as Toll-like receptor 8(TLR8).Experiments revealed that, in DC, snapin is a new medium for HIV-1 transfection of CD4+T cells—which weakens the orientation of HIV-1 and toll-like receptor 8 early endosomes, facilitates transfection of CD4+T cells,and inhibits the pro-inflammatory response (Khatamzas et al., 2017).Other than that, snapin interacts with many molecules to regulate HIV-1 replication and T-cell activation (Zissimopoulos et al., 2006; Wang et al., 2009).Inhibitor peptide Pep 80 can specifically inhibit snapin, thereby inhibiting HIV-1 replication and transcription in T-cells, and this has been confirmed by snapin knockdown experiments (Kinoshita et al., 2013).The latest research also confirms that snapin-mediated macroautophagy/autophagy as a cell stewardship mechanism can remove the accumulation of SNCA aggregates directly related to the dysfunction of motor neurons, and this mechanism is interfered with by HIV-1, which reduces the risk of contracting geriatric degenerative diseases (Santerre et al., 2021).

Significance of snapin for the treatment of other extracerebral disorders

Snapin directly interacts with TPR/MET tyrosine kinase (Schaaf et al., 2005)to modulate hepatocyte growth factor receptor (MET) expression, thereby reducing neuronal apoptosis and improving neurobehavioral function.Studies have shown that the HGF/c-Met axis has a neuroprotective mechanism that mediates anti-apoptotic function (Zheng et al., 2010; Bu et al., 2011), enabling rat models with middle cerebral artery occlusion (MCAO) to form a midbrain artery blockage and then delayed passage, reducing the extent of infarction(Tang et al., 2020).Cells, including tumor cells and vascular endothelial cells, rely heavily on the receptor tyrosine kinase c-Met for production,proliferation, metabolism, and metastasis (Pothula et al., 2020).It is predicted that the snapin protein can become an important target for neurological tumors by modulating c-Met.

Limitations

The main limitation is the huge heterogeneity of snapin on brain homeostatic imbalances.In addition, the expression of Snapin was negatively associated with several health behaviors.For example, the autophagosome-lysosome fusion inducer snapin is down-regulated with age (Kamihara and Murohara,2021).Therefore, we need to consider the heterogeneity when using snapin to treat diseases in elderly patients.There are many factors other than age that need to be considered.The physiological roles involved in snapin are too broad, and therefore, further experiments are required to elaborate and classify the primary and secondary functions of snapin.

Conclusion

Snapin is a critical component of the presynaptic machinery responsible for the homeostatic modulation of vesicle release.Snapin, as an adaptor that interacts with other proteins, achieves multiple biological functions, such as synchronized fusion of synaptic vesicles, growth and development of neurons, and axonal transport of late endosomes and mitochondria.Defects in snapin-mediated pathway have been directly linked to a growing number of brain diseases, including other diseases outside the brain.Therapeutic strategies are designed to target key elements of Snapin proteins to improve neuronal mitochondrial energy metabolism, neuronal death, and neurological dysfunction.Future research should focus on the selectivity of snapin for specific downstream action proteins under disease conditions and identification of small-molecule-binding sites in snapin protein for drug discovery and analysis of protein function.However, this is the gap between snapin as a potential drug target and clinical translation.Despite tremendous efforts by scientists, there is still extensive scope in this field of research.

Author contributions:Conceptualization,MZ,HS;writing—original draftpreparation,JL,XH,YA,HS,MZ;writing—review and revise,JL,XH,YA,XC,YC,MX,HS,MZ;funding acquisition,MZ,HS.All authors have read and agreed to the published version of the manuscript.

Conflicts of interest:The authors declare no conflicts of interest.

Data availability statement:Not applicable.

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