Serotonergic Dysfunction and the Interacting Role of TAR DNA-Binding Protein 43 in the Progression of Amyotrophic Lateral Sclerosis: A Literature Review

1. Introduction

1.1. Rationale

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive neurodegenerative disorder characterized by the degeneration of upper and lower motor neurons, leading to muscle weakness, atrophy, paralysis, and ultimately respiratory failure [1]. Disease onset is heterogeneous, although it is most commonly classified as limb- or bulbar-onset, and only rarely as respiratory-onset ALS. Although traditionally considered a motor disorder, up to 50% of patients exhibit cognitive and behavioral impairments, including executive dysfunction, aphasia, and mood disturbances, indicating the involvement of non-motor brain regions [2,3]. ALS pathogenesis remains poorly understood. Approximately 10% to 15% of cases are familial (fALS), associated with mutations in genes such as C9orf72, SOD1, TARDBP, and FUS [4], while the majority are sporadic (sALS), with no single clearly defined monogenic cause. Environmental factors, including toxin exposure, military service, smoking, and certain occupational exposures, have also been implicated in ALS risk, although their mechanisms remain unclear. Neurodegeneration in ALS may extend beyond the motor cortex to regions other than frontotemporal lobes, such as the basal ganglia, overlapping with patterns observed in Huntington’s and Parkinson’s diseases [5].

A central and increasingly well-defined feature of ALS pathology is protein aggregation, particularly involving the 43-kDa TAR DNA-binding protein (TDP-43). TDP-43 proteinopathy is observed in both fALS and sALS and is thought to “bridge the divide” between these forms of the disease. The few notable exceptions include SOD1- and FUS-linked ALS, in whichTDP-43 proteinopathy appears to be absent [6]. Similar to other neurodegenerative disorders, ALS may involve prion-like spread of misfolded proteins [7]. TDP-43 is tightly regulated, with both depletion and overexpression inducing toxicity [8]. Critically, its mislocalization from the nucleus to the cytoplasm is strongly associated with neuronal toxicity and cell death, with cytoplasmic abnormal TDP-43 serving as a key predictor of toxicity [9]. Despite this, the mechanisms driving TDP-43 mislocalization, aggregation, and propagation remain unclear.

Excitotoxicity is another major contributor to ALS pathology. Glutamate, the primary excitatory neurotransmitter in the central nervous system (CNS), activates N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors to regulate neuronal firing. However, excessive or dysregulated glutamatergic signaling can lead to toxic intracellular calcium accumulation and cell death. This occurs through either elevated extracellular glutamate (“classical” excitotoxicity) or increased neuronal sensitivity to normal glutamate levels (“slow” excitotoxicity)[10]. Given the degeneration of both cortical and spinal motor neurons, excitotoxicity is thought to play a broad role in ALS. Therapeutic support for this hypothesis comes from the success of riluzole, which reduces glutamate toxicity via enhanced glutamate clearance from synaptic clefts [11]. Additionally, dextromethorphan/quinidine (DM/Q), marketed in the United States as Nuedexta®, is a treatment for pseudobulbar affect (PBA), which occurs not infrequently in ALS. The active ingredient, DM has been found to act as a noncompetitive NMDA receptor antagonist, thereby reducing glutamatergic firing and potentially dampening glutamate-mediated excitotoxicity [12]. However, other treatments, such as edaravone (Radicava®), act independently of glutamate (potentially as free radical scavengers), suggesting that excitotoxicity is only one component of a multifactorial disease process [13].

In addition to glutamatergic dysfunction, serotonergic signaling has emerged as a potential contributor to ALS pathogenesis. Serotonin (5-HT) interacts with multiple neurotransmitter systems, including GABAergic, glutamatergic, and dopaminergic pathways [14,15]. Serotonergic projections in the CNS originate primarily from the raphe nuclei (RN) in the brainstem and extend widely to regions involved in motor control, cognition, and emotional regulation, including the cortex, striatum, substantia nigra, and ventral tegmental area [16]. Dysfunction in these pathways may contribute to both motor and cognitive symptoms in ALS and further exacerbate excitotoxic damage by disrupting the balance between excitatory and inhibitory signaling [17]. Notably, extensive pathology in lower RN has been reported in ALS, while the upper RN appears to be only minimally affected by TDP-43 pathology [17]. Taken together, these observations raise the possibility of a modulatory relationship between the serotonergic system and TDP-43 pathology in ALS.

1.2. Objectives

This potential relationship between serotonergic dysfunction and TDP-43 proteinopathy in ALS remains poorly understood. While each of these factors has been independently implicated in disease onset and progression, it is unclear whether, or to what extent, they interact as part of a unified pathogenic mechanism. The relationship between serotonergic signaling and TDP-43 mislocalization and aggregation has not yet been systematically examined.

The primary objective of this study was to conduct a scoping review of the existing literature to evaluate potential mechanistic links between 5-HT and TDP-43 abnormalities in ALS. This included assessing whether serotonergic dysfunction may influence TDP-43 pathology directly or indirectly through modulation of excitotoxic pathways, neuronal hyperexcitability, neuroinflammation, and broader neurotransmitter imbalances.

A secondary objective was to identify common molecular or cellular pathways that may link these processes, with particular attention to calcium signaling, neuronal excitability, and protein homeostasis. By synthesizing findings across genetic, molecular, and systems-level studies, this review aimed to clarify whether these mechanisms converge on common pathogenic processes.

This work also sought to identify gaps in the current literature and highlight promising directions for future experimental research. A clearer understanding of the interaction between serotonergic signaling and TDP-43 pathology may also contribute to the identification of novel therapeutic targets for ALS, particularly those aimed at modulating neurotransmitter systems or preventing protein mislocalization and aggregation.

2. Methods

In this paper, we performed a scoping review to examine the existing literature on the relationship between 5-HT, TDP-43, and the etiology and pathogenesis of ALS. The protocol for this scoping review was developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist (see Supplementary File 1).

2.1. Eligibility Criteria

The authors developed predefined inclusion and exclusion criteria, which were reviewed by the corresponding author. To be included in this review, documents were required to include a substantial explanation of the heritability, etiology and pathophysiological mechanisms underlying ALS. Additionally, documents were required to include, at minimum, a section discussing 5-HT, the serotonergic system, and/or any 5-HT precursors and their interaction with ALS. Finally, documents were required to mention of TDP-43’s role in ALS and/or how TDP-43 interacts with 5-HT or the serotonergic system in ALS.

Papers were included if they were peer-reviewed, published between 1946 and 2026, written in English, and met all three criteria developed by the authors. Papers were excluded if they did not meet all three predefined criteria, or if one or more criteria were mentioned without substantive discussion or sufficient detail to permit meaningful interpretation.

2.2. Information Sources

To identify potentially relevant documents, search strategies were developed in collaboration with an experienced Dentistry-Medicine reference librarian and refined over several meetings. The final search strategy utilized controlled vocabulary (MeSH and Emtree) terms related to ALS, 5-HT, and TDP-43. The full search strategy is provided in Supplementary File 2.

Using the finalized search strategy, the following databases were searched from 1946 to January 28, 2026: Ovid MEDLINE(R) ALL, Embase, EBM Reviews - Cochrane Database of Systematic Reviews, EBM Reviews - Cochrane Central Register of Controlled Trials, Health and Psychosocial Instruments, EBM Reviews - Cochrane Methodology Register, EBM Reviews - Database of Abstracts of Reviews of Effects, EBM Reviews - Health Technology Assessment, EBM Reviews - NHS Economic Evaluation Database, EBM Reviews - ACP Journal Club, EBM Reviews - Cochrane Clinical Answers, BIOSIS Previews, and JBI Best Practice. These databases primarily captured peer-reviewed literature, with limited inclusion of grey literature (e.g. conference abstracts and reports, occasional preprints), but a systematic search of grey literature sources was not conducted. This OVID search was supplemented by manual review of seminal authors’ bibliographies and by screening relevant papers. Final search results were imported into Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia, available at www.covidence.org) for screening. Titles and abstracts were independently screened by two reviewers, followed by full-text assessment of potentially eligible studies. The study selection and screening process were conducted in accordance with PRISMA-ScR guidelines. Screening was performed independently by two reviewers, with discrepancies resolved through discussion.

2.3. Data Charting

Data charting was performed by two reviewers working independently and blinded to each other’s input using Covidence systematic review software. A custom template was used to extract information from the 14 included studies. Following individual data charting, the two reviewers compared their extracted data, and any discrepancies were resolved through discussion until consensus was reached. Extracted data included general study information (e.g., title, study ID, lead author contact details, and date of publication), study characteristics (e.g., aim of study/research question, study design, participant information), as well as results and outcomes related to each of our criteria (e.g. 5-HT relationship with ALS, TDP-43 relationship with ALS, 5-HT relationship with TDP-43). A final version of the charting form is provided in Supplementary File 3.

2.4. Synthesis

The included studies were grouped according to the primary thematic relationship emphasized within each paper (e.g., 5-HT and ALS, TDP-43 and ALS, or 5-HT and TDP-43). Within each group, we summarized study characteristics and broad findings and identified patterns and differences. The evidence was synthesized qualitatively and presented in narrative form.

3. Results

Across the included studies, evidence suggested potential relationships among 5-HT, TDP-43 prion-like propagation, and ALS clinical features. These findings support the need for further research into the connections among 5-HT, TDP-43 propagation, and ALS phenotypes, which may help identify future therapeutic targets.

3.1. Selection of Sources of Evidence

The electronic database search yielded a total of 46 records, as outlined in Figure 1. An additional 8 records were identified through snowball searching, for a total of 54 records. These records were imported into Covidence, where 6 duplicates were identified automatically and 2 manually, leaving 46 unique records for screening. Title and abstract screening resulted in the exclusion of 10 records. The remaining 36 records were sought for retrieval and eligibility assessment. Three full-text records could not be retrieved. An additional 19 records were excluded due to insufficient discussion of 5-HT in ALS (n = 10), insufficient discussion of TDP-43 in ALS (n = 3), wrong population (n = 5), and preprint superseded by published version (n = 1). The remaining 14 studies were included in this review.

3.2. Characteristics of Sources of Evidence

Across the 14 included sources of evidence, study designs included experimental animal studies, randomized and non-randomized analyses, and review literature. Among the experimental studies, transgenic mouse models were used most frequently, followed by Caenorhabditis elegans models, to elucidate specific cellular and mechanistic aspects of ALS in relation to serotonergic dysfunction and TDP-43 pathology. Review articles synthesized the existing literature on serotonergic signaling, including specific 5-HT receptor-mediated mechanisms, cortical hyperexcitability, and potential therapeutic targets in ALS.

Included sources were published between 2012 and 2026, with more than half (57%) published between 2021 and 2026, reflecting growing research interest in this topic. Most papers originated from France (43%) and China (21%). Detailed characteristics of each source are presented in Table 1.

3.3. Results of Individual Sources of Evidence

The key findings from each study, presented in Table A1 (Appendix A), provide a comprehensive overview of the current evidence base.

3.4. Synthesis of Results

The synthesis of results was organized into three thematic groups: (1) the relationship between ALS and 5-HT, (2) the role of TDP-43 in ALS pathogenesis, and (3) the interaction between serotonergic mechanisms and TDP-43 in ALS. Findings across the 14 included studies were summarized within each theme to identify patterns, areas of convergence, and discrepancies in the literature. These papers identified distinct serotonergic alterations in ALS across multiple levels of neurobiological organization, including cellular, circuit, and systems levels.

4. Discussion

The findings of this review suggest that the relationship between serotonergic dysfunction and TDP-43 pathology may help elucidate the complex pathophysiology underlying ALS. Further research is needed to clarify the links between serotonergic signaling and TDP-43 proteinopathy and to determine whether these pathways may represent viable therapeutic targets in ALS.

4.1. Summary of Evidence

4.1.1. ALS and 5-HT

Available evidence supports an association between 5-HT and ALS, although the nature of this relationship remains incompletely defined. A consistent finding was the early and widespread impairment of central serotonergic systems, which appears to precede or accompany key pathological features of ALS rather than simply arise as a downstream consequence of motor neuron degeneration [18,19,20]. Twelve of the 14 analyzed papers supported the presence of serotonergic impairment in ALS, while the remaining two described serotonergic system alterations without confirming a role in disease progression.

One of three most consistent observations was a reduction in 5-HT levels and serotonergic innervation in both ALS patients and animal models [17,19,21,22]. Reduced platelet 5-HT levels in a subset of patients, coupled with a positive correlation with survival, suggest that serotonergic dysfunction may carry prognostic [17,18,22]. Because plasma 5-HT cannot cross the blood–brain barrier, these peripheral findings may reflect dysfunction within the CNS [20,23]. This interpretation is supported by experimental data showing degeneration of serotonergic neurons in the RN, together with loss of their projections to the hippocampus and hypothalamus in the forebrain and to the spinal cord [19,20,21,23]. Importantly, in SOD1 mice, loss of serotonergic function is found to occur presymptomatically, suggesting that this dysfunction may contribute early in ALS pathogenesis [18,19,22].

5-HT plays a key role in modulating motor neuron excitability, with alterations in the serotonergic system contributing to hyperexcitability and spasticity [18,20]. Several authors [18,19,20] generally agree that loss of serotonergic input leads to compensatory changes, including upregulation and constitutive activation of 5-HT2B/2C receptors, which in turn increase motor neuron excitability [19,20]. Although this contributes to spasticity, El Oussini et al. [24] note it may also represent a compensatory mechanism, as reducing serotonergic-driven spasticity can worsen motor performance and accelerate disease progression in ALS models [18,21]. This highlights 5-HT’s multifaceted role, suggesting it may exert both protective and pathological effects.

5-HT may also be relevant to ALS through its relationship with glutamate-mediated excitotoxicity. Serotonergic denervation may reduce inhibitory control over glutamate release via presynaptic receptors, thereby exacerbating excitotoxic damage [17,22]. Brunet et al. [20] also highlight how 5HT directly modulates persistent inward currents and calcium conductances in motor neurons, thereby contributing to sustained excitability. Together, these mechanisms position serotonergic dysfunction as a potential drive of excitatory-inhibitory imbalance observed in ALS.

A substantial body of pharmacological research has attempted to clarify 5-HT’s role in ALS, but findings remain mixed. Jiang et al. [25] used three different 5-HT receptor antagonists to evaluate the effects of different receptor subtypes on disease progression. Interestingly, all three drug classes reduced body weight in transgenic mice but did not accelerate disease onset or shorten survival. These findings suggest a potential protective role for 5-HT in disease progression. Arnoux and Dupuis [18] noted that administration of 5-hydroxytryptophan improves survival and locomotor function in SOD1 mouse models, suggesting similar benefits from enhancing serotonergic tone and function. In contrast, selective serotonin reuptake inhibitors (SSRIs), including fluoxetine and paroxetine, can exacerbate disease progression and increase cortical excitability, particularly when administered early in development [18,20] is important to note that these differing outcomes may be related to timing of administration, specifically neonatal rather than adult treatment in transgenic mice. Arnoux and Dupuis [18] also noted that monoamine oxidase-B inhibition with rasagiline has shown limited but suggestive clinical benefit, potentially through modulation of 5-HT metabolism. Altogether, these mixed pharmaceutical findings suggest that timing, dosage, and mechanism of serotonergic modulation may all be important. Further studies controlling for these factors may help identify future therapeutic targets, both presymptomatically and after symptom onset.

Only recently have different 5-HT receptor subtypes been investigated as exerting distinct effects in ALS, and this area warrants further study. 5-HT receptor subtype 2B (5-HT2B) appears to mediate some of the protective effects described by El Oussini et al. [24] 5-HT depletion leads to overexpression of 5-HT2B receptors and subsequent constitutive receptor activity during the development of spasticity [19], suggesting a compensatory mechanism that may help preserve motor function [24]. El Oussini et al. [24] build on this by demonstrating that 5-HT2B upregulation in ALS transgenic mouse models promotes microglial survival and slows disease progression, while its ablation significantly accelerates progression. In contrast, 5-HT2A receptor signaling in astrocytes contributes to neuroinflammation and oxidative stress, particularly in later disease stages, where its inhibition improves motor neuron survival and extends lifespan in mouse models [26]. Jiang et al. [25] also evaluated the effects of receptor subtypes 2, 3, and 4, finding that inhibitors of 5-HT3 reduced body weight in transgenic mice, whereas inhibition of 5-HT2 and 5-HT4 worsened motor function. These differing results underscore the importance of further research into specific 5-HT receptor subtypes, some of which may be protective whereas others may exacerbate disease progression.

Serotonergic dysfunction also extends beyond motor systems to influence metabolic and hypothalamic pathways. Reduced hypothalamic 5-HT levels and compensatory upregulation of 5-HT2C receptors disrupt melanocortin signaling, contributing to altered feeding behavior and hypermetabolism in ALS models [23]. Given that weight loss is associated with poorer prognosis, these findings highlight a broader systemic role for 5-HT in ALS progression.

Recent research supports a potentially protective role of 5-HT in disease progression, as the receptor antagonists studied in Jiang et al. [25] worsened several motor and disease-related features in transgenic mouse models of ALS. This aligns with clinical observations that higher 5-HT levels are associated with reduced mortality risk [22]. However, the precise role of 5-HT remains complex, as both insufficient and excessive, or mistimed, serotonergic signaling may be detrimental.

Taken together, these findings support a model in which ALS involves an early, progressive disruption of serotonergic systems, contributing to motor dysfunction, neuroinflammation, metabolic changes, and excitatory-inhibitory imbalances. 5-HT appears to exert both protective and pathological effects depending on receptor subtype, disease stage, and cell type, which likely explains the variability experimental and review-based results. Further work should prioritize targeted, receptor-specific investigation across different stages of disease in order to clarify the therapeutic potential of the serotonergic system in ALS.

4.1.2. ALS and TDP-43

TDP-43 is a well-established pathological hallmark of several neurodegenerative diseases, including ALS and frontotemporal dementia (FTD). Compared with the emerging and more complex association between ALS and serotonergic dysfunction, the involvement of TDP-43 in ALS is relatively well established. Accordingly, our analysis focused primarily on whether the findings reported in our studies aligned with the broader body of literature. Overall, the extracted data were largely consistent with prior work.

TDP-43, encoded by the TARDBP gene, is a DNA/RNA-binding protein that plays a critical role in RNA metabolism, including transcription, splicing, and transport [27]. In ALS, pathological alterations in TDP-43 are observed in approximately 97% of cases, regardless of whether mutations in the TARDBP gene are present [18]. These alterations include mislocalization of TDP-43 from the nucleus to the cytoplasm, where it forms aggregates. This mislocalization leads both to loss of critical nuclear function and gain of toxic cytoplasmic function, contributing to widespread cellular dysfunction, including oxidative stress and impaired RNA processing [18,27]. Abnormal cytoplasmic TDP-43 is also believed to spread between cells through a prion-like process of seeding and propagation [7].

Beyond aggregation, several studies highlighted the broad metabolic and cellular consequences of TDP-43 dysfunction, much of which stems from loss of its essential nuclear functions. Disruption of RNA homeostasis, altered gene expression, and downstream effects on protein synthesis and cellular maintenance pathways collectively contribute to neuronal vulnerability and degeneration [18]. These mechanisms reinforce the central role of TDP-43 as a driver of cellular pathology in multiple regions of the nervous system in ALS, most prominently within motor-related areas.

Taken together, these findings reaffirm that TDP-43 proteinopathy is a unifying feature of ALS, characterized by largely consistent molecular, cellular, and anatomical patterns across studies. Although the core mechanisms of TDP-43 dysfunction are relatively well-established, its presence in regions associated with broader neuromodulatory systems highlights important avenues for further investigation, particularly in understanding how canonical ALS pathology may intersect with less-explored systems such as 5-HT.

4.1.3. TDP-43 and 5-HT in ALS

Emerging evidence suggests that serotonergic dysfunction and TDP-43 proteinopathy are mechanistically interconnected in a complex and potentially bidirectional manner. Although this relationship remains incompletely defined, the studies reviewed here support a model in which TDP-43 pathology disrupts serotonergic signalling early in disease progression, while serotonergic dysfunction may in turn influence the propagation and severity of TDP-43 pathology.

Central to this interpretation is the possibility that TDP-43 pathology impairs serotonergic function at a cellular and synaptic level before overt neuronal loss occurs. In C. elegans models, expression of human TDP-43 variants produced graded impairments of 5-HT-dependent behaviours, with cytoplasmically mislocalized TDP-43 causing the most severe deficits [28]. These phenotypes suggest that TDP-43 disrupts serotonergic signaling through functional impairment, such as altered neurotransmitter synthesis and release, or receptor signaling, rather than via complete degeneration of serotonergic neurons. This aligns with previous observations that TDP-43 may compromise neuromodulatory systems, including 5-HT, before neuronal death occurs [29]. Brunet et al. [20] further support this interpretation by describing the effects of TDP-43 pathology on inhibitory synaptic transmission, which may also be linked to altered serotonergic function and destabilized motor circuits. At the systems level, these disruptions likely contribute to network dysfunction and imbalances between excitation and inhibition, a hallmark of ALS. Given 5-HT’s central role in modulating both excitatory and inhibitory inputs, it is reasonable to suspect that serotonergic dysfunction may amplify these effects. Indeed, Koopman et al. [30] demonstrated that motor circuit imbalance underlies TDP-43-induced paralysis, with altered neuromodulatory input contributing to reduced functional output. The authors noted potential serotonergic influence on cholinergic neurons, which may suppress their activity. Furthermore, this paper [30], highlighted how cellular changes caused by TDP-43 toxicity can render normal serotonergic signalling maladaptive. In their model, circuit dysfunction begins with TDP-43-induced degeneration of GABAergic neurons, disrupting motor circuit balance, while serotonergic signalling continues to suppress cholinergic motor neuron activity. In a balanced circuit, this serotonergic inhibition is necessary to regulate motor output; however, in a dysfunctional circuit, this suppression becomes detrimental and produces subsequent deficits in locomotion.

It is also important to consider that this interaction may operate in the reverse direction. Pharmacological evidence suggests that disruption of serotonergic signaling can exacerbate TDP-43 pathology. In ALS mouse models, administration of 5-HT receptor antagonists increased TDP-43 expression, promoted its cytoplasmic mislocalization, and increased the number of TDP-43-positive cells [25]. Using transgenic (Tg) and wild-type (WT) mice, Jiang et al. [25] examined the effects of granisetron, piboserod, and ritanserin, antagonists for 5-HT3, 5-HT4, and 5-HT2 receptors, respectively. Antagonism of each receptor subtype consistently worsened TDP-43 pathology, increasing TDP-43 expression, accumulation, and cytoplasmic mislocalization, while also promoting neuroinflammation and neuronal loss; however, these treatments did not accelerate disease progression or shorten survival in Tg mice. Altogether, these findings support the idea that 5-HT may play a protective or stabilizing role in maintaining TDP-43 homeostasis, and that loss of serotonergic tone may accelerate pathological aggregation processes [25].

This relationship is further complicated by cell-specific differences in vulnerability and pathology. In addition, while TDP-43 pathology is most commonly associated with motor systems, evidence indicates that its distribution extends beyond classical motor circuits. Dentel et al. [19] reported the presence of TDP-43 aggregates in regions with dense serotonergic innervation, such as the raphe magnus and gigantocellular nuclei. However, there is also evidence that serotonergic neurons themselves may be relatively resistant to typical TDP-43 aggregation. Vermeiren et al. (2018) demonstrated that the upper RN which give rise to diffuse cortical projections, appear to be relatively spared from TDP-43 pathology in ALS, raising the possibility that specific serotonergic populations may exert protective effects or possess intrinsic resistance to protein aggregation. El Oussini et al. [21] similarly reported a lack of TDP-43 inclusions within serotonergic neurons, suggesting that these cells may possess unique mechanisms for clearing aggregation-prone proteins. Potential explanations for these discrepancies include regional differences within the RN, as well as differences among the models studied. Taken together, this evidence raises the possibility that serotonergic dysfunction in ALS arises more from functional impairment and circuit-level disruption than from intracellular aggregate toxicity within serotonergic neurons themselves.

The spatial propagation of TDP-43 pathology may also relate to this interpretation. Multiple studies support a prion-like spreading mechanism, in which misfolded and mislocalized TDP-43 propagates through neural networks over time [17,22]. Early environmental exposures may also trigger long-term neurodevelopmental vulnerabilities; for instance, neonatal exposure to the neurotoxin BMAA has been shown to produce persistent monoaminergic dysregulation and neuropathological changes characteristic of neurodegenerative disease [31]. Degeneration of serotonergic projections, or early deposition of pathological proteins within their target regions, may contribute to widespread monoaminergic imbalance, affecting not only motor function but also behavioural and cognitive domains [17]. There is reason to believe this prion-like propagation and serotonergic dysfunction are related, although the exact mechanism remains unresolved. As noted by Vercruysse et al. [23], 5-HT-related deficits, such as disruptions in melanocortin signaling, may influence, or be influenced by, the spread of TDP-43 aggregates, although the paucity of comparable research highlights an important gap in the literature.

In their discussion of melanocortin signaling, emerging work by Vercruysse et al. [17] points to a potential role of the gut–brain axis in linking these processes. Phosphorylated TDP-43 aggregates have been detected in the gastrointestinal tract before symptom onset, suggesting that ALS pathology may begin in the enteric nervous system and spread to the CNS [22]. Given that 5-HT is a key mediator of the gut-brain-microbiome axis, this raises the intriguing possibility that peripheral serotonergic signaling may influence early TDP-43 pathology or its propagation. If confirmed, such a mechanism would further support a systemic, rather than purely central, view of ALS pathogenesis.

Taken together, these multifaceted findings support a model in which TDP-43 proteinopathy and serotonergic dysfunction are interconnected across multiple levels of disease progression. TDP-43 may disrupt serotonergic signaling early through synaptic and molecular mechanisms, thereby contributing to circuit dysfunction and hyperexcitability. Conversely, serotonergic deficits may exacerbate TDP-43 aggregation and propagation, either by removing protective influences or by altering cellular homeostasis. The apparent resistance of serotonergic neurons to protein aggregation, despite functional impairment, further underscores the complexity of this relationship.

Overall, this potential bidirectional relationship highlights the need to move beyond single-pathway explanations of ALS and instead adopt a more integrated framework in which protein aggregation, neuromodulatory dysfunction, and network-level disturbances converge to drive disease progression. Future research should prioritize clarification of the mechanistic links between TDP-43 and 5-HT, particularly in relation to protein propagation, synaptic regulation, and the gut-brain axis, in order to better inform the development of targeted and temporally precise therapeutic strategies.

4.2. Limitations

As a scoping review, this study has several limitations. It was not designed to provide definitive or causal conclusions, but rather to synthesize the existing evidence and identify gaps in a complex and underexplored area. Although data extraction was conducted by two independent reviewers, the small number of reviewers introduces a risk of selection and interpretation bias. In addition, the limited inclusion of grey literature may contribute to publication bias, as unpublished or negative findings are likely underrepresented. There is also potential for search and selection bias related to database limitations, keyword choices, and possible exclusion of relevant studies. Moreover, this review did not include a formal critical appraisal of included sources of evidence (PRISMA-ScR Item 12). Although omission of critical appraisal is consistent with PRISMA-ScR guidance for scoping reviews, the lack of quality assessment limits the ability to evaluate the methodological rigor and risk of bias of the included studies. Considerable heterogeneity across studies, including differences in experimental models (human, mouse, and C. elegans), methodologies, and outcome measures, limits direct comparison and may reduce generalizability. This is particularly relevant because many mechanistic insights are derived from animal models, which may not fully reflect human ALS pathology. Finally, the relative scarcity of studies directly examining interactions between 5-HT and TDP-43 necessitates reliance on indirect evidence, which may introduce interpretive assumptions when proposing mechanistic links.

5. Conclusions

Although complex and multifaceted, this review highlights a potential relationship between TDP-43 proteinopathy and serotonergic dysfunction in ALS. Further experimental research is needed to clarify the nature and directionality of this relationship, particularly with careful consideration of disease stage and model system (e.g. C. elegans, rodent, or human patient). A more precise understanding of the relationship between 5-HT and TDP-43 may help identify novel therapeutic targets, potentially including the gut-brain axis or more specific 5-HT receptor subtypes (e.g., 5-HT2B).