Role of RNA-binding proteins in exercise-induced mRNA regulation: Unveiling biomarkers and therapeutic targets for schizophrenia

Abstract

This article summarizes recent advances in the understanding of RNA-binding proteins (RBPs), with a focus on their roles in exercise-induced mRNA regulation and their implications for schizophrenia (SZ). RBPs are critical regulators of mRNA stability, splicing, transport, translation, and degradation, directly influencing gene expression through sequence- and structure-specific binding. In the nervous system, RBPs sustain synaptic plasticity, neural development, and neuronal homeostasis. Emerging evidence shows that exercise modulates the expression and activity of RBPs, thereby influencing mRNA translation and neurotransmitter signaling, which may underlie its beneficial effects on brain function. Dysregulation of specific RBPs has been identified in SZ, implicating them in disrupted synaptic transmission, impaired plasticity, and neuroinflammation. RBPs involved in memory and emotional regulation show marked dysfunction in SZ patients. Some RBPs have been proposed as potential biomarkers for early diagnosis and treatment monitoring. Moreover, therapeutic modulation of RBPs, through pharmacological or behavioral interventions such as exercise, may restore neuronal function by targeting post-transcriptional gene regulation. Exercise, as a non-invasive modulator of RBP expression, holds promise as an adjunctive strategy in SZ treatment, particularly in early stages. Further research into RBP-mediated pathways may offer novel insights into SZ pathophysiology and inform the development of targeted interventions.

Key Words: RNA-binding proteins; Exercise-induced; mRNA; Schizophrenia; Biomarkers; Therapeutic targets

Core Tip: This review highlights recent insights into RNA-binding proteins (RBPs) and their regulatory roles in exercise-induced mRNA expression, with a special focus on schizophrenia (SZ). RBPs control mRNA stability, translation, and localization, which are critical for neural function and synaptic plasticity. Exercise modulates the expression and function of specific RBPs, potentially improving neurotransmission and neural health. Abnormal RBP expression is linked to SZ pathophysiology, and certain RBPs may serve as biomarkers or therapeutic targets. Our findings suggest that exercise may be a promising adjunctive intervention to regulate RBPs and mitigate SZ symptoms.

INTRODUCTION

Schizophrenia (SZ) is a prevalent and severe mental disorder that affects approximately 0.3% to 0.7% of the global population[1,2]. It is characterized by a diverse range of symptoms, including cognitive impairments, emotional disturbances, and hallucinations, typically manifesting during adolescence or early adulthood[1]. Despite extensive research, the precise etiology of SZ remains elusive. It is widely believed, however, that its pathogenesis is driven by complex interactions between genetic predispositions, environmental factors, and neurobiological processes[3]. Currently, the treatment of SZ remains inadequate, with antipsychotic medications primarily targeting neurotransmitter systems such as dopamine and glutamate, yet failing to address the cognitive and negative symptoms of the disorder. These limitations highlight a pressing need for novel therapeutic strategies that can more comprehensively address SZ’s multifaceted nature, particularly its cognitive and neurodevelopmental components.

Recent evidence suggests that disruptions in RNA regulation, particularly through RNA-binding proteins (RBPs), play a pivotal role in the pathogenesis of SZ. RBPs are key post-transcriptional regulators that influence mRNA stability, translation, splicing, and degradation[4]. These proteins are essential for maintaining synaptic function, neural development, and neuroplasticity, all of which are critically impaired in SZ[5,6]. The role of RBPs in regulating gene expression in the nervous system has been increasingly recognized, and their dysfunction is believed to contribute to the cognitive decline and synaptic deficits seen in SZ patients.

In recent years, studies have also shown that exercise may modulate RBP expression, offering potential benefits for SZ treatment. Exercise has been demonstrated to enhance the expression of genes involved in neuroplasticity and neurodevelopment, such as brain-derived neurotrophic factor (BDNF), which supports neurogenesis and synaptic function[7]. Moreover, exercise can influence RBP function, improving mRNA stability and translation efficiency, which in turn may help restore normal synaptic activity and improve cognitive and emotional health in SZ patients[4,7].

This review provides a comprehensive overview of the role of RBPs in SZ, with a particular focus on how exercise can modulate RBP expression as a potential therapeutic intervention. First, we summarize the critical roles of RBPs in synaptic plasticity, cognitive function, and neurodevelopment. We then explore how exercise-induced changes in RBP expression may provide therapeutic benefits, particularly by addressing the neurodevelopmental deficits and cognitive impairments in SZ. Finally, we highlight selective RBPs implicated in SZ etiology, including fragile X mental retardation protein (FMRP), RNA binding fox-1 homolog (RBFOX1), TAR DNA-binding protein 43 (TDP-43), and human antigen R (HuR), discussing how these proteins contribute to the pathogenesis of the disorder and how exercise might influence their expression to improve SZ symptoms. Through this exploration, we aim to clarify the molecular mechanisms by which exercise influences RBP function in SZ and offer insights into how these interventions could be integrated into clinical strategies to improve outcomes for individuals with SZ.

OVERVIEW OF RBP IN SZ

SZ is a complex neurodevelopmental disorder that affects various brain functions, including cognition, emotional regulation, and synaptic plasticity[8]. While the detailed pathogenesis of SZ remains elusive, increasing evidence suggests that RBPs play a pivotal role in its development and progression[9]. RBPs are essential post-transcriptional regulators that impact mRNA stability, splicing, translation, and degradation, which in turn influence gene expression and neuronal function[10]. Dysfunction in RBPs has been implicated in the neurobiological disruptions observed in SZ patients, such as impaired synaptic plasticity and neurodevelopmental abnormalities[11,12].

Recent studies have demonstrated that exercise can influence the expression and function of RBPs, offering a promising avenue for improving neuroplasticity and cognitive function in SZ[13]. Exercise-induced changes in RBPs, such as enhanced stability and translation of mRNAs related to synaptic function, can mitigate the neurodevelopmental deficits seen in SZ[7]. Furthermore, the regulation of RBPs by exercise appears to have therapeutic potential, particularly in alleviating both cognitive and emotional symptoms of SZ by promoting synaptic plasticity and restoring normal neural function[8].

The altered expression and function of specific RBPs in SZ patients can disrupt critical processes such as mRNA stability, synaptic plasticity, and neurodevelopment[14]. For instance, the abnormal regulation of RBPs involved in synaptic transmission, like FMRP and TDP-43, has been associated with cognitive and emotional dysfunction in SZ[5,6]. Understanding how exercise can modulate these RBPs is crucial for developing new therapeutic strategies for SZ. Exercise, by enhancing RBP function, may improve neuroplasticity, potentially restoring normal neural circuitry that is disrupted in SZ[7].

Given the significant role of RBPs in SZ, and the ability of exercise to modulate these proteins, exercise-based interventions may serve as a novel adjunctive therapy. Exercise not only regulates mRNA translation and stability but also improves the expression of key RBPs that contribute to the restoration of synaptic function and neural plasticity. This review explores the mechanisms by which exercise influences RBPs in SZ and highlights how such interventions can support the treatment of SZ, especially in the early stages of the disorder.

MECHANISMS OF RBPS

Basic functions and classification of RBPs

RBPs are a class of proteins that specifically bind to RNA molecules, performing critical roles in post-transcriptional regulation[15]. By interacting with RNA, RBPs impact RNA fate, namely stability, translation, splicing, localization, and degradation[11]. A recent review by Schneider-Lunitz et al[12], implicates that RBPs are essential for normal RNA metabolism within cells and function by recognizing specific sequences or structural features of RNA. It is worth noting that translational regulatory RBPs. bind to the 5’ or 3’ untranslated regions (UTRs) of mRNA to regulate translational efficiency. For example, eukaryotic translation initiation factor 4E initiates translation by attaching to the 5’ cap structure of mRNA[16], while HuR binds to the 3’ UTR to impact translation and transport[17]. Splicing RBPs, recognize splice sites on precursor mRNA and regulate alternative splicing[18]. Proteins such as SR proteins (e.g., SRSF1) and heterogeneous nuclear ribonucleoproteins, regulate splice site selection, performing crucial roles in gene diversity and cell-specific expression[18]. Stability regulatory RBPs, control mRNA stability by attaching to the 3’ UTR, shaping mRNA half-life[19]. For instance, RBPs like AU-rich element RNA-binding protein 1 and tristetraprolin (TTP), bind AU-rich elements (AREs) in the 3’ UTR to enhance mRNA degradation, whereas HuR increases stability and boosts translation efficiency by attaching to the same region[19]. Transport and Localization RBPs, regulate the transport and localization of mRNA within the cell[20]. For example, zipcode binding protein 1, binds specific sequences on mRNA to transport it to cellular compartments such as dendrites or axon terminals, which is vital for neuronal function[20]. Mechanisms of interaction between RBPs and mRNA is demonstrated in Figure 1.

Figure 1 Mechanisms of interaction between RNA binding proteins and mRNA. This figure illustrates how RNA binding proteins (RBPs) regulate their fate by attaching to different regions of the mRNA. This figure is divided into three main modules: Translational regulation, stability regulation, and regulation of degradation and half-life. In translational regulation, RBPs initiate or inhibit translation by attaching to the 5’ untranslated region (UTR) or 3’ UTR regions of mRNAs, such as tristetraprolin proteins and cytoplasmic polyadenylation element-binding protein proteins. In stability regulation, RBPs regulate mRNA stability by attaching to the 3’ UTR, AU-rich element RNA-binding protein 1 and tristetraprolin bind AU-rich regions to enhance degradation, while human antigen R increases mRNA stability and improves translation efficiency. In the regulation of degradation and half-life, RBPs enhance or prevent mRNA degradation through specific sequence recognition, e.g., Pumilio RNA-binding protein 2 enhances degradation and human antigen R prevents degradation to enhance stability. RBPs: RNA binding proteins; AREs: AU-rich regions; TTP: Tristetraprolin; HuR: Human antigen R; PUM2: Pumilio RNA-binding protein 2.

Interaction between RBPs and mRNA

RBPs are crucial for regulating mRNA fate by attaching to specific regions of mRNA, participating in various post-transcriptional modifications such as translation, stability, splicing, and localization[18]. These interactions count on sequence recognition or secondary structural binding, which not only govern the post-transcriptional fate of mRNA but also have profound effects on gene expression regulation[19-27]. RBPs can regulate translation by attaching to the 5’ UTR or 3’ UTR of mRNA to initiate or inhibit translation. For instance, the TTP protein, binds to sequences in the 3’ UTR to inhibit translation of immune-related genes[24]. Another example is cytoplasmic polyadenylation element-binding protein (CPEB), which regulates the length of the polyadenylate tail to impact translation[25]. Despite advancements, further studies are needed to investigate the regulatory mechanisms of various RBPs under specific physiological or pathological conditions[26]. Beyond translation, RBPs are pivotal in mRNA stability control. Many RBPs bind specific sequences in the 3’ UTR to regulate stability. For example, AU-rich element RNA-binding protein 1 and TTP, bind to AREs to enhance degradation[27]. Conversely, proteins like HuR, preserve mRNA and increase translation efficiency by attaching to the 3’ UTR[28]. The regulation of mRNA stability by RBPs is across different cell types, highlighting the complexity of gene expression regulation within cells[29]. RBPs also impact mRNA degradation through interactions with specific sequences, such as AREs. Pumilio RNA-binding protein 2 is a classic example, attaching to the 3' UTR to enhance mRNA degradation[27]. Conversely, RBPs like HuR, increase stability and translation efficiency by preventing degradation[30,31].

Relationship between RBPs and SZ

Currently, studies increasingly emphasize the critical role of RBPs in SZ, particularly in the regulation of neurodevelopment, neuroplasticity, and synaptic function. Abnormal neurodevelopment is a hallmark of SZ, especially in critical regions like the cortex and hippocampus[32]. RBPs such as FMRP, are pivotal in neural differentiation, synaptic formation, and neural circuit remodeling. FMRP deficiency has been associated with SZ susceptibility, as it regulates mRNA stability and local translation to impact synaptic function and plasticity[33]. Neuroplasticity, the ability of neurons to alter synaptic connections in response to environmental changes, is regulated by RBPs, particularly in synaptic plasticity modulation. RBPs such as CPEB and FMRP, which participate in processes like long-term potentiation, show expression abnormalities in SZ patients, likely affecting cognitive functions and emotional regulation[34]. Synaptic dysfunction is a core pathological feature of SZ. RBPs, namely TDP-43, regulate synaptic protein expression and perform crucial roles in synaptic formation and function. Abnormal TDP-43 aggregation is associated with SZ and other neurodegenerative diseases[35]. Research shows that abnormal expression of certain RBPs, such as FMRP, TDP-43, and RBFOX1, correlates with SZ symptoms (e.g., cognitive impairment and emotional dysregulation)[33]. This implicates that abnormal RBPs expression is a molecular hallmark of SZ, likely contributing to the disorder’s clinical symptoms through impacts on neuroplasticity and synaptic function. Further research is needed to clarify the specific molecular mechanisms and pathways through which RBPs impact SZ development, with the aim of discovering new diagnostic and therapeutic targets for the disorder (Figure 2).

Figure 2 Relationship between RNA binding proteins and schizophrenia. This figure depicts the relationship between the roles of RNA binding proteins (RBPs) in schizophrenia (SZ), showing how RBPs are associated with SZ symptoms by shaping neurodevelopment, neuroplasticity, and synaptic function. RBPs have been associated with neurodevelopmental abnormalities through their impact on the role of fragile X mental retardation protein (FMRP) in neural differentiation and synapse formation. RBPs (e.g., cytoplasmic polyadenylation element-binding protein and FMRP) regulate synaptic plasticity and have been associated with impaired cognitive and affective functioning in SZ patients. TAR DNA-binding protein 43 in RBPs plays a crucial role in synaptic function and its abnormalities have been associated with SZ. The relationship between abnormal expression of RBPs (especially FMRP, cytoplasmic polyadenylation element-binding protein, and TAR DNA-binding protein 43) and SZ symptoms, such as cognitive impairment and affective dysregulation, is demonstrated below. RBPs: RNA binding proteins; FMRP: Fragile X mental retardation protein; SZ: Schizophrenia; CPEB: Cytoplasmic polyadenylation element-binding protein; TDP-43: TAR DNA-binding protein 43.

THE IMPACT OF EXERCISE ON RBPS

Effects of exercise on RBPs expression and function

Exercise, as a non-specific physiological stimulus, can substantially impact the expression and function of RBPs through various pathways. These effects extend to neural activity, hormone level changes, and cellular stress responses, likely shaping gene expression and, consequently, the adaptability of the nervous system[36]. Exercise performs a crucial role in enhancing neural plasticity and coping with physiological and environmental challenges (Figure 3)[37].

Figure 3 Mechanism of the effect of exercise on the expression and function of RNA binding proteins. The figure starts with exercise and describes its regulation of RNA binding proteins (RBPs) through three major pathways - neural activity, hormonal changes, and cellular stress. Role of RBPs. In the neural activity pathway, exercise activated brain-derived neurotrophic factor, N-methyl-D-aspartate receptors, and calcium signaling pathways to regulate RBPs such as cytoplasmic polyadenylation element-binding protein and human antigen R to enhance synaptic function and neuroplasticity. The hormonal change pathway reveals that exercise raises the levels of brain-derived neurotrophic factor and stress hormones (e.g., cortisol), which alters RNA stability and translation efficiency. The cellular stress pathway, on the other hand, reveals that exercise-induced oxidative stress and heat stress ultimately support gene expression and adaptation in the nervous system by activating RBPs such as stress proteins (e.g., Hsp70), TAR DNA-binding protein 43, and fused in sarcoma. BDNF: Brain-derived neurotrophic factor; NMDA: N-methyl-D-aspartate; CPEB: Cytoplasmic polyadenylation element-binding protein; HuR: Human antigen R.

Neural activity and RBPs regulation: In recent years, research on the regulatory role of neural activity on RBPs has gradually increased. Previous studies have shown that exercise can enhance neural plasticity, regulate synaptic function, and neuronal adaptation by activating BDNF and other molecules such as N-methyl-D-aspartate receptors and calcium signaling pathways[38,39]. Through N-methyl-D-aspartate receptor-mediated calcium signaling, exercise regulates the expression of RBPs such as CPEB and HuR, which play important roles in synaptic function and neuroplasticity[40]. However, although these studies emphasize the potential mechanism by which exercise alters the expression and function of RBPs through neural activity, there is still some controversy. For example, there is no consensus on whether different types of exercise (such as aerobic exercise and strength training) have different regulatory effects on RBPs. Some studies suggest that strength training may have a significant impact on some RBPs (such as CPEB), while aerobic exercise has a significant effect on other RBPs (such as HuR), but the results of different studies often differ due to differences in sample size, exercise type, and intervention duration. Future research should further explore the specific effects of different types of exercise on RBPs, especially how the regulatory role of RBPs changes under various exercise intervention conditions. Relying solely on one type of exercise may not fully demonstrate the impact of exercise on neural plasticity, therefore more cross type and cross population research is needed to reveal the role of exercise in neural adaptation.

Hormonal changes and RBPs regulation: The role of hormone regulation induced by exercise in the expression and function of RBPs has also received widespread attention. Exercise increases BDNF levels and enhances the expression of neurohormones closely related to neural plasticity[40]. BDNF further affects the synthesis of RBPs by activating the transcription factor CREB, thereby regulating neural function and synaptic plasticity[41]. In addition, exercise can also promote the release of stress hormones such as cortisol and norepinephrine, which have a significant impact on the adaptability of the nervous system[42]. However, there is still significant uncertainty regarding the mechanism by which exercise regulates RBPs expression through hormones. There is no consensus on the differences in the effects of exercise types (such as aerobic exercise and strength training) on hormone secretion in different studies. This difference may be related to individual differences (such as age, gender, etc.) as well as the intensity and duration of exercise interventions. Some studies suggest that certain forms of exercise may cause sharp fluctuations in hormone levels, which may further affect the expression of RBPs, and this effect may vary among individuals. Therefore, future research should focus on revealing the specific regulatory relationship between hormone signaling pathways and RBPs, especially through which hormone pathways different types of exercise regulate RBPs. This can help us gain a deeper understanding of the long-term impact of hormone changes on neural adaptation.

Cellular stress and RBPs regulation: Exercise, especially high-intensity exercise, can trigger cellular stress responses, leading to oxidative stress, heat stress, and metabolic stress. These stress responses activate stress-related signaling pathways within cells, such as p38 mitogen-activated protein kinase and c-Jun N-terminal kinase, thereby regulating the activity of RBPs and affecting neurological function[43]. Previous studies have shown that stress proteins such as Hsp70 can regulate their stability by binding to mRNA, helping cells maintain normal function under stress conditions[44]. In addition, exercise induced oxidative stress can also activate RBPs related to DNA repair and anti-inflammatory responses, such as TDP-43 and fused in sarcoma (FUS), which play key roles in neurodegenerative diseases and neurodevelopmental processes[45]. Although these studies provide preliminary evidence for the relationship between exercise induced cellular stress and RBPs regulation, existing research still has certain limitations, especially in the unclear mechanism of the interaction between cellular stress and RBPs. Although some studies have shown that oxidative stress and heat stress can affect RBPs expression through different signaling pathways, there is still no consistent research conclusion, especially on how these stress responses affect the regulatory mechanisms of RBPs under different types of exercise, which is still unclear.

Exercise-induced changes in brain RBPs

Exercise directly impacts RBP expression in the brain by altering neural activity and specific regions of the brain, thus adjusting the nervous system’s structure and function[46]. Brain regions, such as the hippocampus and prefrontal cortex, respond differently to exercise, presenting distinct RBP expression patterns linked to memory, emotional regulation, and cognitive function[46]. This implicates that the effects of exercise on the brain extend beyond general neural activation and involve region-specific molecular regulation[4]. While research has demonstrated how exercise alters RBPs in the hippocampus and prefrontal cortex, more studies are needed to clarify the specific roles of exercise type and intensity on RBPs expression across various brain regions (Figure 4).

Figure 4 Mechanisms of exercise-induced changes in brain RNA binding proteins. This figure demonstrates how exercise exerts a multilevel modulatory effect on brain function by shaping RNA binding protein (RBP) expression in different brain regions. Exercise activates multiple brain regions, namely the hippocampus, prefrontal cortex, cerebral cortex, striatum, and cerebellum, with each region responding uniquely to the expression of RBPs. In the hippocampus, enhanced expression of RBPs such as human antigen R, CPEB, and cytoplasmic polyadenylation element-binding protein enhances memory and learning ability; in the prefrontal cortex, the role of TAR DNA-binding protein 43 contributes to emotion regulation and cognitive flexibility; and in the cerebellum, the regulation of RNA binding fox-1 homolog contributes to motor coordination. This figure reveals the region-specific regulation of RBPs in the brain by exercise, which in turn has a profound effect on neural function. HuR: Human antigen R; CPEB: Cytoplasmic polyadenylation element-binding protein; FMRP: Fragile X mental retardation protein; TDP-43: TAR DNA-binding protein 43; RBFOX1: RNA binding fox-1 homolog.

RBPs changes in the hippocampus: The hippocampus is a critical area for learning, memory, and spatial cognition, particularly responsive to exercise interventions. Research has shown that exercise can significantly stimulate the expression of some important RBPs (such as HuR, CPEB, and FMRP) in the hippocampus, which play a crucial role in hippocampal plasticity[47]. For example, FMRP is an RBPs crucial for neural development, which enhances neuronal response to synaptic stimuli by regulating mRNA translation related to synaptic plasticity and memory formation, thereby improving learning and memory function[8]. Although previous studies have shown that FMRP plays an important role in exercise induced hippocampal plasticity, there is still controversy about how exercise regulates the expression and function of these RBPs in different types of exercise (such as aerobic exercise and strength training).

RBPs changes in the prefrontal cortex: The prefrontal cortex is an important area for executive function, decision-making, and emotional regulation. Exercise intervention can alter the expression of RBPs in this region, especially in genes related to emotion regulation and cognitive flexibility[48]. For example, TDP-43 is closely related to synaptic function and neural plasticity in the prefrontal cortex[49].

Although existing research has identified the critical role of TDP-43 in synaptic function in the prefrontal cortex, there are still significant limitations in how movement regulates RBPs in this region. Most studies focus on animal models, while there are relatively few clinical studies on humans. More importantly, the specific regulatory mechanism of exercise on prefrontal cortex RBPs is still unclear, and future research requires more refined experimental designs to explore the effects of different types of exercise on the expression of prefrontal cortex RBPs, especially in clinical populations.

Effects of exercise on RBPs in other brain regions: In addition to the hippocampus and prefrontal cortex, exercise also affects the expression of RBPs in other brain regions such as the cerebral cortex, striatum, and cerebellum, thereby affecting learning, memory, motor coordination, and emotional regulation. For example, exercise activates RBFOX1 in the cerebellum, which is a crucial RBPs for cerebellar nerve development and motor coordination[50,51].

However, there is still a lack of consistent conclusions in existing literature regarding the specific effects of exercise on RBPs in these brain regions, particularly how to regulate their expression through different types of exercise. Some studies have shown that RBFOX1 in the cerebellum plays a crucial role in motor interventions, however, the research results show significant differences between different forms of exercise, exercise intensity, and individual differences (such as age, gender, etc.)[52]. For example, the regulatory effect of aerobic exercise on RBPs in the cerebral cortex and striatum may differ from that of strength training[53]. Therefore, future research should focus on the specific regulatory effects of different types of exercise on RBPs expression, especially in terms of affecting motor coordination, emotional regulation, and cognitive function.

Regulation of SZ-related RBPs by exercise

SZ is a severe neuropsychiatric disorder, often distinguished by cognitive deficits, emotional fluctuations, and thought disorders. Studies indicate that the onset of SZ is tightly associated with the abnormal expression of specific RBPs[54]. Since RBPs perform critical roles in gene expression regulation, neural plasticity, and synaptic transmission, exploring whether exercise can mitigate or alleviate abnormal RBPs expression is a promising area for investigation (Figure 5).

Figure 5 Regulatory mechanisms of RNA binding proteins associated with schizophrenia through exercise. This figure demonstrates the mechanism of regulation of the expression of RNA binding proteins (RBPs) associated with schizophrenia through exercise. The figure first appears the association between schizophrenia and aberrant expression of RBPs, specifically RNA binding fox-1 homolog expression is decreased in prefrontal cortex PVI cells from schizophrenia patients. Exercise regulates the expression of several RBPs (e.g., human antigen R, cytoplasmic polyadenylation element-binding protein, and TAR DNA-binding protein 43) by enhancing synaptic plasticity and neuroplasticity, thereby restoring normal synaptic transmission function to some extent. In addition, exercise positively alters neurodevelopment by increasing the health of brain structures (e.g., promoting neurogenesis and hippocampal volume increase) and increasing brain-derived neurotrophic factor levels, thereby improving cognitive function and emotional stability in SZ patients. SZ: Schizophrenia; HuR: Human antigen R; CPEB: Cytoplasmic polyadenylation element-binding protein; TDP-43: TAR DNa-binding protein 43; RBFOX1: RNA binding fox-1 homolog.

Exercise regulation of SZ-related RBPs: Research has shown that the expression of RBFOX1 is significantly regulated in SZ, especially in PVI cells of the prefrontal cortex, where the protein level of RBFOX1 is reduced[55]. RBFOX1, as a key RNA binding protein, plays an important role in synaptic transmission. However, there is still controversy regarding whether exercise can improve synaptic function in SZ patients by regulating the expression of RBFOX1. Some studies suggest that exercise may indirectly restore the function of RBFOX1 by enhancing the expression of growth factors such as BDNF, while other studies have not shown similar effects. In addition, the regulation of RBFOX1 may be influenced by multiple factors, such as the type of exercise (aerobic exercise vs strength training), the intensity and frequency of exercise, and an individual's genetic background. Therefore, future research should further explore how different types of exercise specifically regulate the expression of RBFOX1 and evaluate its potential application in SZ treatment.

The neuroplastic effects of exercise: Exercise is widely believed to promote synaptic plasticity and partially restore normal neural circuit function in the brain. Research has shown that exercise positively affects various aspects of brain function, such as increasing synaptic and cerebrovascular plasticity, which are key to supporting neural connectivity and function. Specifically, exercise can restore essential circuits in motor behavior by modulating dopamine and glutamate neurotransmission, and by influencing overall brain physiology. Studies like those by Lu et al[56] and Petzinger et al[57] highlight how physical activity contributes to the enhancement of brain plasticity and the improvement of both cognitive and motor circuits in individuals, particularly in conditions like Parkinson's disease. In this context, exercise may help restore synaptic function by regulating the expression of RBPs such as HuR, CPEB, and TDP-43, thereby improving cognitive impairment and emotional stability in SZ patients[58]. Although previous studies have shown that exercise has been shown to improve neuroplasticity and cognitive function, potentially by enhancing the function of RBPs. Bherer et al[59] highlight that physical activity promotes neuroplasticity, and exercise-mediated neuroplasticity plays a key role in rehabilitation, particularly in regaining lost motor function after a stroke. However, the current body of research also indicates significant heterogeneity in the results. As Amjad et al[60] note, although aerobic exercise has demonstrated therapeutic effects on electroencephalography parameters and higher cognitive functions in mild cognitive impairment patients, the outcomes can vary across studies, suggesting the complexity of the relationship between exercise and cognitive enhancement. Some studies have shown that exercise has been shown to improve cognitive function by enhancing the expression of TDP-43, which is associated with neuroprotection and brain health. For example, Sofi et al[61] highlighted that exercise can improve cognition, reduce age-related brain volume loss, and impede neurodegeneration, supporting the notion that physical activity benefits cognitive function. However, some studies have failed to replicate these findings in clinical or animal models. Kreiner et al[62] demonstrated that riluzole treatment did not alter disease progression in a transgenic mouse model expressing TDP-43, suggesting that the expected improvements in cognitive function related to TDP-43 expression may not always be observed. Therefore, future research should focus on the specific mechanisms by which exercise regulates RBPs, particularly the differences in effectiveness among different forms of exercise interventions and individual populations.

Effects of exercise on neurodevelopment: The neurodevelopmental hypothesis suggests that SZ may originate from early brain structural abnormalities and functional impairments[63]. Research has shown that exercise can improve brain function in SZ patients by promoting cognitive function, hippocampal volume, neurogenesis, and synaptic plasticity, and increase levels of growth factors such as BDNF[64]. Although these studies have revealed the potential benefits of exercise for neural development, particularly in SZ patients, there are still many challenges. Firstly, the specific mechanism of neurodevelopmental disorders in SZ is not yet clear, and existing research mostly focuses on animal models, lacking large-scale clinical empirical data. In addition, there is controversy over the impact of exercise on neural development at different stages, especially for SZ patients who have already developed the disease. It is still unclear whether exercise can effectively improve early brain structural abnormalities. Future research should explore how exercise affects the pathogenesis of SZ, particularly in early intervention, by regulating the expression of specific RBPs.

ROLE OF RBPS-REGULATED MRNA STABILITY AND TRANSLATION IN SZ

Abnormalities in mRNA stability and translation in SZ

In SZ patients, the mechanisms regulating mRNA stability and translation are substantially impaired. This dysregulation may perform a critical role in neurodevelopment, synaptic function, neural network remodeling, and neurodegenerative processes[65]. Studies indicate that abnormalities in mRNA stability and translation contribute to SZ pathogenesis, likely and directly, impacting neuronal function and synaptic plasticity[66]. Exploring these abnormalities will increase our understanding of SZ pathology and potential therapeutic strategies (Table 1).

Table 1 Mechanisms of RNA binding protein-regulated mRNA stability and translation and exercise regulation in schizophrenia.

Aspects	Key RBPs	Description	Functions and effects	Ref.
Abnormal mRNA stability	TDP-43, FUS	Research centers on the pathological changes in RBPs related to mRNA degradation and stability, such as TDP-43 and FUS, in neurons and glial cells of schizophrenia patients, possibly accelerating specific mRNA degradation	Impaired mRNA stability alters critical gene expression, exacerbating schizophrenia pathogenesis	[71]
Abnormal translation regulation	FMRP, CPEB	Abnormal mRNA translation in schizophrenia is often linked to RBP dysfunction, particularly the roles of FMRP and CPEB in synaptic translation regulation	Alters synaptic structure and function, regulating neural plasticity; abnormalities may contribute to synaptic network disruption	[72]
Effects on neurodevelopment and neurodegeneration	TDP-43, FMRP, CPEB	Abnormal mRNA stability and translation may disrupt neurodevelopmental processes, shaping neuronal connectivity and information processing, thus aggravating schizophrenia symptoms	Impacts synapse formation and pruning in the cortex and hippocampus, damaging neural networks	[77]
RBPs and synaptic function	FMRP, CPEB	Decreased FMRP expression in the brains of schizophrenia patients may contribute to synaptic dysfunction, impacting learning and memory. CPEB plays a crucial role in post-synaptic translation regulation	Abnormal expression linked to impaired post-synaptic translation regulation, shaping learning and memory capacity	[37]
RBPs and neural network remodeling	RBFOX1	RBFOX1 plays a key role in synapse formation and neural connectivity regulation; its dysfunction may contribute to abnormal network connections, causing cognitive impairment	Dysfunction leads to abnormal neural network connections, shaping cognitive function	[76]
RBPs and inflammatory response	HuR	HuR regulates the intensity and duration of immune responses by stabilizing and controlling mRNA expression of inflammation-related genes; abnormalities may contribute to excessive immune activation, worsening neuroinflammation	Plays a role in regulating inflammation gene expression; abnormalities may worsen neuroinflammation	[77]
Exercise impact on mRNA translation and stability	HuR, FMRP	Exercise substantially increases the expression of RBPs such as HuR and FMRP, helping regulate mRNA translation in synaptic plasticity and neurodevelopment	Improves synaptic function impaired by abnormal mRNA translation and stability	[81]
Exercise regulation of neurodevelopment and immune genes	BDNF, IL-6	Exercise regulates gene expression related to neurodevelopment and immune response, impacting mRNA stability and translation efficiency, which may help alleviate schizophrenia symptoms	Improves neurodevelopment and immune response, likely alleviating schizophrenia symptoms	[83]
Exercise’s role in synaptic plasticity and neural network restoration	FMRP, TDP-43	Exercise enhances synaptic plasticity, axonal transport, and neural network remodeling through RBPs like FMRP and TDP-43, restoring normal neural network function	Enhances functional recovery of neural networks, enhancing connectivity and plasticity	[53]

RBPs: RNA binding proteins; FMRP: Fragile X mental retardation protein; TDP-43: TAR DNA-binding protein 43; FUS: Fused in sarcoma; CPEB: Cytoplasmic polyadenylation element-binding protein; RBFOX1: RNA binding fox-1 homolog; HuR: Human antigen R; BDNF: Brain-derived neurotrophic factor; IL-6: Interleukin-6.

mRNA stability abnormalities in neurons and glial cells of SZ patients have become a focal point of research. RBPs tightly associated with mRNA degradation and stability, such as TDP-43 and FUS, which are implicated in neurodegenerative diseases, may have similar roles in SZ[66]. Pathological changes in TDP-43 and FUS could accelerate the degradation of specific mRNAs, causing neuronal dysfunction. For instance, dysfunction in TDP-43 and FUS disrupts mRNA stability in neurons, shaping the expression of critical genes and likely contributing to SZ pathogenesis[66]. It is noteworthy that mRNA translation abnormalities in SZ patients are often linked to RBP dysfunction, particularly proteins like FMRP and CPEB, which have essential roles in post-synaptic translation regulation[67]. FMRP, impacts synaptic structure and function by regulating the local translation of target mRNAs, thereby controlling neural plasticity[68]. The CPEB family of proteins, which execute critical roles in synaptic translation and neural network remodeling, also present functional abnormalities in SZ, likely causing network-level disruptions and exacerbating clinical symptoms[25]. One proposed SZ pathology is abnormal neurodevelopment, especially in synaptic formation and pruning in regions such as the cortex and hippocampus, processes essential for normal development[69]. Abnormalities in mRNA stability and translation may disrupt these developmental processes, shaping neuronal connectivity and information processing and ultimately intensifying SZ symptoms[70].

Role of RBPs in SZ

RBPs carry out crucial roles in the pathogenesis and progression of SZ. Evidence increasingly illustrates that specific RBPs present abnormal expression and function in the brains of SZ patients, which is tightly associated with pathologies such as synaptic dysfunction, neural network remodeling, and neuroinflammation (Table 1).

Proper synaptic function is essential for neural system stability, with RBPs performing key roles in this process. The significant reduction of FMRP expression in the brains of SZ patients is one of the potential reasons for impaired synaptic function, tightly associated with learning and memory dysfunction[37]. In addition, CPEB has a vital role in post-synaptic translation regulation, with abnormalities in its expression linked to neuropsychiatric disorders, especially SZ[37]. SZ’s neural network abnormalities are tightly associated with RBP dysfunction. RBFOX1, an RBP crucial for synaptic formation and neural connectivity regulation, may contribute to aberrant neural network connections when its function is impaired, causing SZ symptoms like cognitive impairment[71]. Neuroinflammation has recently been confirmed as a crucial component of SZ pathogenesis. Immune dysregulation, particularly aberrant inflammatory responses, is a foundation of SZ onset. RBPs like HuR hold a vital role in this process by stabilizing and regulating mRNA expression of inflammation-related genes, adjusting the intensity and duration of immune responses[72]. Abnormal HuR function in SZ patients may contribute to excessive immune activation, exacerbating neuroinflammation[73].

The potential of exercise in regulating mRNA translation and stability

Exercise is widely confirmed for its significant effects on physical health and has also been demonstrated in recent years to have a potential role in neuroprotection and neuroadaptation. Particularly in therapeutic studies of psychiatric disorders such as SZ, exercise has been suggested to play a positive role in repairing aberrant mechanisms related to mRNA translation and stability by regulating the expression of RBPs, which may play a positive role in repairing mRNA translation and stability. These specific mechanisms are reflected in Table 1.

The impact of exercise extends beyond physical improvement; it substantially alters the expression of specific RBPs by regulating neural activity, hormone levels, and cellular stress responses[74]. For example, exercise substantially increases the expression of RBPs such as HuR and FMRP, which conduct essential roles in synaptic plasticity and mRNA translation processes associated with neural development. Enhancing these RBPs’ functions may provide new therapeutic avenues for treating SZ-related synaptic dysfunction owing to mRNA translation and stability abnormalities[75]. In addition, abnormal neurodevelopment and immune dysregulation are tightly associated SZ[76]. Exercise, as a multifunctional intervention, impacts genes associated with neurodevelopment and immune responses, shaping mRNA stability and translation efficiency[77]. Specifically, exercise regulates the expression of key genes such as BDNF and interleukin-6, impacting mRNA translation processes associated with neurodevelopment and immune responses, likely alleviating SZ symptoms[78]. It is worth noting that in SZ treatment research, the beneficial effect of exercise on RBP regulation, offers a new perspective on improving neural network function[79]. Synaptic plasticity and neural network remodeling are essential for normal neural system function, with RBPs such as FMRP and TDP-43 achieving key roles in this process[79]. By regulating mRNA translation associated with synaptic plasticity, axonal transport, and neural network remodeling, these RBPs boost neuronal connectivity, likely restoring normal neural network function[53].

RBPS AS BIOMARKERS AND THERAPEUTIC TARGETS IN SZ

The potential of RBPs in SZ has gained increasing recognition, particularly in early diagnosis and monitoring disease progression. As a complex neurodevelopmental disorder, the exact pathogenesis of SZ continues to be controversial, and early symptoms are often subtle, lacking definitive biological markers[80,81]. Therefore, discovering effective biomarkers for the onset and progression of SZ is a primary research focus. owing to their crucial role in neurodevelopment, RBPs are increasingly thought of as potential biomarkers and therapeutic targets for SZ. Table 2 outlines RBPs as biomarkers and therapeutic targets for SZ[37,82-84].

Table 2 RNA binding protein as biomarkers and therapeutic targets in schizophrenia.

Biomarker	Mechanism of action	Therapeutic target	Ref.
FMRP	Downregulation of FMRP is associated with synaptic dysfunction, likely impacting cognitive deficits	Improve cognitive ability by restoring normal FMRP function to treat cognitive impairments	[37]
TDP-43	Excessive aggregation of TDP-43 is linked to neurodegeneration and impaired synaptic remodeling	Target TDP-43 aggregation to slow neurodegenerative changes	[82]
RBFOX1	Downregulation of RBFOX1 is associated with abnormalities in neurodevelopment and synaptic function	Use gene therapy to reinstate RBFOX1 function and improve cognitive deficits	[83]
CPEB	CPEB performs a key role in synaptic plasticity and neurodevelopment	Regulate CPEB expression through RNA interference to improve synaptic function and neuroplasticity	[84]

FMRP: Fragile X mental retardation protein; TDP-43: TAR DNA-binding protein 43; RBFOX1: RNA binding fox-1 homolog; CPEB: Cytoplasmic polyadenylation element-binding protein.

RBPs as biomarkers

Abnormal expression and dysfunction of RBPs in SZ may support their role as biomarkers. Studies have demonstrated significant changes in the expression of certain RBPs in the brains of SZ patients, tightly associated with clinical symptoms. Thus, RBPs expression patterns might reflect the onset and progression of SZ[37]. Dysfunction of these RBPs is observed not only in brain tissue but also in peripheral tissues such as blood and skin cells, making them potential non-invasive biomarkers for SZ diagnosis[85].

Research illustrates significant changes in the expression of RBPs such as FMRP, TDP-43, and RBFOX1 in SZ patients’ brains. Specifically, the downregulation of FMRP, abnormal aggregation of TDP-43, and alterations in RBFOX1 are tightly linked to SZ clinical manifestations[5]. FMRP and RBFOX1 downregulation is directly associated to synaptic dysfunction, while excessive TDP-43 aggregation may contribute to neurodegeneration and impaired synaptic remodeling[82]. These abnormalities not only indicate dysregulation in neuronal communication but also reveal possible molecular mechanisms underlying SZ. Early diagnosis of SZ is challenging owing to subtle symptoms and diagnostic delays, and there is currently no effective biomarker for clinical screening[86]. Recently, the potential use of RBPs for early SZ diagnosis has attracted widespread attention. Studies suggest that downregulation of FMRP and RBFOX1 is tightly associated with SZ pathogenesis, providing a new avenue for early diagnosis[77,78]. Detecting RBP expression in blood, saliva, or skin cells could be a viable method for early identification of SZ, allowing intervention before prominent symptoms manifest and likely improving clinical outcomes[5,87]. SZ progression often involves cognitive decline, neurodegeneration, and fluctuating psychiatric symptoms[88]. RBPs’ expression changes may indicate disease activity and progression. TDP-43 accumulation, for example, is linked not only to acute episodes but also to the chronic progression of SZ, making RBPs useful tools for disease monitoring and prognosis evaluation[89]. Monitoring RBPs’ expression changes in peripheral tissues could provide clinicians with a new, real-time disease tracking method.

RBPs as therapeutic targets

With a growing understanding of role of RBPs in SZ, RBPs are now seen as potential therapeutic targets, in addition to their role as biomarkers[5]. RBPs have crucial roles in SZ pathology, especially in regulating synaptic transmission and neural network remodeling[10].

A core pathological feature of SZ is impaired synaptic transmission and neural network remodeling. An article has shown that RBPs such as FMRP, TDP-43, and CPEB, are critical for synaptic plasticity and neurodevelopment, shaping neural function and cognitive performance by regulating gene expression[38]. Restoring FMRP function may help improve post-synaptic translation regulation and cognitive ability. Thus, targeting RBPs like FMRP may offer new treatment approaches for SZ-related cognitive impairment[90]. Gene therapy, as a potential treatment, has been widely considered for SZ. Repairing the function of RBPs such as RBFOX1 through gene-editing technologies could be key in alleviating SZ symptoms[91]. RBFOX1 is an essential factor in neurodevelopment regulation, with downregulation tightly linked to SZ pathogenesis[88]. Restoring RBFOX1 function may repair its role in neurodevelopment, thereby improving cognitive and psychiatric symptoms associated with SZ[91]. RNA interference offers new possibilities for targeting RBPs in SZ treatment[9,92]. Techniques such as RNA interference, antisense oligonucleotides, and CRISPR-Cas9 can regulate RBPs expression to alleviate SZ symptoms[9,92]. For example, silencing overexpressed RBPs with siRNA or shRNA, or restoring deficient RBPs expression through antisense RNA technology, could regulate mRNA translation and stability, enhancing synaptic function and neuroplasticity[89]. This strategy enables precise RBP regulation, providing a personalized approach to SZ treatment.

This review underscores the pivotal role of RBPs in the pathophysiology of SZ, particularly in regulating mRNA stability, translation, and synaptic function. We have discussed how dysregulation of RBPs contributes to the cognitive, emotional, and neuroplasticity deficits observed in SZ patients. In addition, we explored how exercise can modulate RBP expression, offering promising therapeutic potential for improving these aspects of SZ. Exercise-induced changes in key RBPs, such as HuR, CPEB, and TDP-43, enhance synaptic function and neuroplasticity, which may help alleviate both cognitive and emotional symptoms of SZ.

Despite significant progress in understanding the role of RBPs in SZ, several challenges remain. These include the unclear mechanisms by which exercise regulates RBPs, the high heterogeneity among exercise intervention studies, and the limited empirical data from human populations. While animal models and in vitro studies have provided valuable insights, the translation of these findings into human clinical settings remains a significant hurdle. Thus, while promising, further research is crucial to unravel the full therapeutic potential of exercise-induced RBP modulation in SZ treatment.

FUTURE RESEARCH DIRECTIONS

To advance the field, future studies should focus on delineating the precise molecular mechanisms by which exercise regulates RBPs in SZ. A comprehensive understanding of the specific signaling pathways activated by different types of exercise - such as aerobic, strength training, or cognitive exercises - will be crucial. Furthermore, the heterogeneity among exercise protocols, including variations in intensity, duration, and participant characteristics, necessitates standardized approaches to identify optimal exercise parameters that maximize therapeutic effects on RBPs and SZ symptomatology. Longitudinal studies assessing the long-term impact of exercise on neurodevelopment, cognitive function, and emotional regulation in SZ patients are also needed to establish exercise as a reliable adjunctive therapy.

Moreover, clinical trials directly investigating the effects of exercise on RBP expression in human SZ patients are critical. Given the current lack of large-scale human studies, much of the understanding regarding exercise-induced changes in RBP function remains speculative. The integration of advanced technologies such as neuroimaging, gene expression profiling, and biomarker discovery will play a key role in translating molecular findings into clinical practice.

CLINICAL PROSPECTS AND CHALLENGES

The potential of exercise as an adjunctive treatment for SZ is promising, particularly given the limitations of current pharmacological treatments, which are often associated with side effects and limited efficacy in treating cognitive and negative symptoms. Exercise offers a non-pharmacological alternative with broad neuroprotective effects, making it a valuable addition to SZ management. However, several clinical challenges remain. Personalized exercise programs tailored to individual patient needs, taking into account factors such as disease severity, cognitive function, and comorbidities, will be essential for maximizing therapeutic outcomes. Additionally, barriers to the implementation of exercise interventions in clinical settings - such as patient motivation, accessibility, and adherence - must be addressed. Developing more engaging and accessible exercise regimens, along with training healthcare providers to incorporate exercise into patient care plans, will be pivotal in overcoming these challenges.

OPPORTUNITIES FOR INTERDISCIPLINARY COLLABORATION

The complex nature of SZ and the multifaceted effects of exercise on brain function necessitate interdisciplinary collaboration. Neurologists, psychiatrists, exercise physiologists, and molecular biologists must work together to bridge the gap between molecular mechanisms and clinical outcomes. Collaboration between neuroscience and exercise physiology will help clarify the neural circuits involved in exercise-induced changes in RBP expression. Molecular biologists can contribute by identifying specific RBPs and signaling pathways modulated by exercise, while psychiatrists and psychologists can assess the behavioral and cognitive outcomes of exercise interventions.

Moreover, the development of new technologies, such as wearable devices for monitoring exercise and biomarkers for RBP regulation, can further enhance the precision and personalization of exercise interventions. These innovations will allow for real-time assessment of the impact of exercise on RBP expression and SZ symptoms, paving the way for more effective and individualized treatment strategies.

CONCLUSION

In conclusion, the intersection of exercise and RBP regulation offers a promising frontier in SZ treatment. Although significant challenges remain in understanding the underlying molecular mechanisms and translating these findings into clinically effective treatments, the potential for exercise to serve as a therapeutic tool for SZ is increasingly evident. As research continues to evolve, it is vital to address critical questions, such as whether different forms of exercise exert distinct effects on RBP regulation, to optimize the therapeutic application of exercise in SZ, thereby improving the quality of life for those affected by this debilitating disorder.