Currently, no curative therapies exist for Amyotrophic Lateral Sclerosis (ALS). This study aimed to evaluate the efficacy and safety of Huoling Shengji granules (HLSJ), a traditional Chinese medicine (TCM), compared to the standard treatment riluzole. A multicenter, randomized, double-blind, double-dummy, active-controlled Phase II clinical trial was conducted across 11 centers in China. A total of 140 ALS patients were randomly assigned (1:1) to receive either HLSJ or riluzole for 48 weeks. The primary endpoint, analyzed in the full analysis set (FAS), was the change in the ALS Functional Rating Scale-Revised (ALSFRS-R) score from baseline to Week 48. Safety profiles were comparable between groups, with no significant difference in adverse events (80.28% vs. 80.56%, P = 0.9671). Analysis using the pre-specified Last Observation Carried Forward (LOCF) method showed a numerical advantage for HLSJ (1.07 points) but lacked statistical superiority. However, a more scientific analysis using the Mixed Model for Repeated Measures (MMRM), recommended for progressive diseases, indicated that HLSJ was significantly superior to riluzole in slowing ALSFRS-R score decline (Least Squares Mean Difference [LSMD]: 2.29 points; 95% confidence interval [CI]: 0.52 to 4.06; P = 0.0114). While the LOCF model showed no statistical difference, the MMRM analysis confirmed that HLSJ demonstrated significant efficacy superior to riluzole with a favorable safety profile. These findings provide a critical basis for conducting pivotal Phase III confirmatory trials of HLSJ for ALS treatment.

BACKGROUND:RIPK1, a protein regulating inflammatory signalling and cell death, is implicated in amyotrophic lateral sclerosis (ALS) pathophysiology. SAR443820 is a selective, oral, CNS-penetrant, reversible RIPK1 inhibitor. We aimed to evaluate the safety, tolerability, and efficacy of SAR443820 in participants with ALS. METHODS:This multicentre, randomised, double-blind, placebo-controlled, phase 2 trial was conducted at 63 clinical sites in 13 countries (Belgium, Canada, China, France, Germany, Italy, Japan, the Netherlands, Poland, Spain, Sweden, the UK, and the USA). Adults (aged 18-80 years) with a diagnosis of possible ALS, clinically probable ALS, clinically probable laboratory-supported ALS, or clinically definite ALS, in accordance with the revised El Escorial World Federation of Neurology criteria, were randomly assigned (2:1) by use of a stratified block design (blocks of three) to receive either 20 mg SAR443820 orally twice per day or matching placebo in the 24-week double-blind period. Randomisation was done centrally using interactive response technology and stratified by geographical region of trial site, region of ALS onset, use of riluzole, use of edaravone, and use of the combination of sodium phenylbutyrate and taurursodiol. Participants, care providers, investigators, and outcomes assessors were masked to trial intervention. The primary outcome was a change in ALS Functional Rating Scale Revised (ALSFRS-R) total score from baseline to week 24 and was calculated for all participants who had an ALSFRS-R total score available at baseline and at week 24. Safety analyses included all randomly assigned participants receiving one dose or more of trial intervention. This trial is registered with ClinicalTrials.gov (NCT05237284) and was terminated early. FINDINGS:Between April 13, 2022, and July 17, 2023, 397 participants were screened and 305 randomly assigned to SAR443820 (n=203) or placebo (n=102); six were excluded from the primary analysis due to missing baseline ALSFRS-R values. Mean age was 56·9 years (SD 11·5); 183 (60%) participants were male and 122 (40%) were female. Least squares mean change in ALSFRS-R from baseline to week 24 was -6·73 (95% CI -7·48 to -5·98) for SAR443820 group (n=169) and -6·32 (-7·36 to -5·27) for placebo group (n=87). There was no statistically significant difference between the study groups (least squares mean difference -0·41 [95% CI -1·71 to 0·88]). Participants in the SAR443820 group had higher incidence of adverse events (171 [85%] of 202 vs placebo 80 [78%] of 102) and treatment discontinuations (28 [14%] of 202 vs placebo five [5%] of 102), with elevated hepatic enzymes being the most common cause. Nine deaths occurred in the double-blind period (seven [3%] of 202 in the SAR443820 group and two [2%] of 102 in the placebo group); none was attributed to SAR443820. INTERPRETATION:SAR443820 did not show clinical benefit and was associated with higher hepatic enzyme increase, indicating that further clinical development of SAR443820 in ALS is not warranted. FUNDING:Sanofi.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with progressive loss of motor neurons. Insufficiency of neurotrophic factors is suspected to underlie the disease, but direct evidence remains scarce. In this study, we discover that brain-derived neurotrophic factor (BDNF) val/met mutation, which results in a decrease in BDNF secretion, reduces survival time of ALS patients in two separate cohorts. Using a knockin mouse model of the ALS causal gene FUSR521C, we demonstrate that BDNF haploinsufficiency leads to shortened lifespan, accelerated motor dysfunctions, and exacerbated motor neuron death. Importantly, activation of the BDNF receptor TrkB by an agonistic antibody effectively rescues these ALS-associated phenotypes. In additional ALS mouse models, TrkB activation antibody also shows superior therapeutic effects compared to current ALS medication riluzole. Our data indicate that insufficient BDNF could be a crucial contributing factor for ALS progression, and activation of BDNF-TrkB pathway may represent a promising therapeutic strategy against ALS.

Parkinson's disease (PD) is an incurable neurological disorder that often begins insidiously with sleep disturbances and somatic symptoms, progressing to whole-body motor and cognitive symptoms1-5. Dysfunction of the somato-cognitive action network (SCAN)-which is thought to control action execution6,7 by coordinating arousal, organ physiology and whole-body motor plans with behavioural motivation-is a potential contributor to the diverse clinical manifestations of PD. To investigate the role of the SCAN in PD pathophysiology and treatments (medications, deep-brain stimulation (DBS), transcranial magnetic stimulation (TMS) and MRI-guided focused ultrasound stimulation (MRgFUS)), we built a large (n = 863), multimodal, multi-intervention clinical imaging dataset. Resting-state functional connectivity revealed that the substantia nigra and all PD DBS targets (subthalamic nucleus, globus pallidus and ventral intermediate thalamus) are selectively connected to the SCAN rather than to effector-specific motor regions. Importantly, PD was characterized by specific hyperconnectivity between the SCAN and the subcortex. We therefore followed six PD cohorts undergoing DBS, TMS, MRgFUS and levodopa therapy using precision resting-state functional connectivity and electrocorticography recording. Efficacious treatments reduced SCAN-to-subcortex hyperconnectivity. Targeting the SCAN instead of effector regions doubled the efficacy of TMS treatments. Focused ultrasound treatment benefits increased when the target was closer to the thalamic SCAN sweet spot. Thus, SCAN hyperconnectivity is central to PD pathophysiology and its alleviation is a hallmark of successful neuromodulation. Targeting functionally defined subcortical SCAN nodes may improve existing therapies (DBS, MRgFUS), whereas cortical SCAN targets offer effective non-invasive or minimally invasive neuromodulation for PD.

AIM:To explore how grip strength is related to functional status and health-related quality of life (HRQoL) in amyotrophic lateral sclerosis (ALS) patients. METHODS:In the phase 2 trial of TBN for treatment of ALS, 148 patients in full analysis set received TBN (600 mg or 1200 mg) or a placebo for 180 days. Outcome measurements included ALS Functional Rating Scale-Revised (ALSFRS-R), 40-item ALS Assessment Questionnaire (ALSAQ-40), grip strength, and forced vital capacity (FVC). Spearman's rank correlation was used to examine associations between grip strength, ALSFRS-R and ALSAQ-40. A principal component analysis-ANCOVA model adjusted for sex was used to further explore the associations. RESULTS:Grip strength was strongly correlated with ALSFRS-R fine motor function domain (rs = 0.740) and moderately correlated with ALSAQ-40 activities of daily living (ADL) domain (rs = -0.637) (p < 0.05). Weak correlations were observed between FVC and both ALSFRS-R total score (rs = 0.355) and respiratory domain (rs = 0.229) and ALSAQ-40 domains. Grip strength was a strong predictor of ALSFRS-R fine motor and ALSAQ-40 ADL domains. CONCLUSION:Grip strength was associated with functional status and HRQoL, supporting its potential role as a meaningful clinical outcome measure in patients with ALS.

Peripheral factors that systemically regulate amyotrophic lateral sclerosis (ALS) have remained elusive-until now. Here, by integrating population-scale epidemiology with mechanistic dissection, we identify platelet factor 4 (PF4) as the central driver of a circulating neuroprotective axis that restores proteostasis and rescues ALS. In a prospective cohort of >500 000 UK Biobank participants, platelet indices were strongly associated with ALS risk, and serum PF4 levels were significantly reduced in ALS patients. Systemic administration of recombinant PF4 in hSOD1G93A mice produced dramatic therapeutic effects: extended survival, preserved motor function, attenuated neuroinflammation, and reduced neuromuscular junction denervation. Remarkably, this efficacy appears pathology-selective-robust in SOD1-driven models but shows no observable effect in TDP-43 or C9orf72 ALS models. Mechanistically, PF4 achieves what few molecules can: it engages the cell surface receptor LRP1 to activate the TBK1-OPTN signaling axis, restoring impaired autophagic flux through a PINK1/Parkin-independent pathway requiring ATG7, establishing a previously unrecognized peripheral platelet-autophagy-neuron axis that facilitates the co-clearance of pathological SOD1 aggregates and damaged mitochondria. This study unveils PF4 as a first-in-class circulating autophagy regulator with therapeutic potential in ALS. Beyond identifying a candidate biomarker and drug lead, it reveals that systemic factors can directly engage central proteostatic machinery-opening a new frontier for ALS therapy.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with multifactorial causes, including genetic and environmental factors. This study aimed to identify environmental and lifestyle factors influencing the progression of ALS by leveraging the first and largest patient-reported ALS database in China (the AskHelpU ALS Patient Platform), addressing a critical gap in regional research. Data from 1421 patients with ALS, including detailed information on occupational exposure, lifestyle habits, dietary patterns, and medical history, were collected from the AskHelpU platform. Statistical analyses were conducted to identify associations between these factors and clinical characteristics. The associations between pre-onset factors and disease progression were analyzed using multicariable generalized linear models, adjusting for multiple comaparisons with the Bonferroni correction. Employment in the agriculture industry (p < 0.001) was associated with rapid ALS progression, whereas employment in the leasing and business services industry (p = 0.01) and education industry (p = 0.033) slowed ALS progression. Other key pre-onset prognostic factors were cigarette smoking (p = 0.043) and pre-existing hypertension (p = 0.036). By utilizing the patient-reported ALS database, this study comprehensively examined the effects of environmental, occupational, and lifestyle factors on ALS progression. These findings provide novel insights into the regional variations in ALS etiology, emphasizing the multifactorial nature of the disease.

Background/Objectives: Emerging evidence suggests that enlarged perivascular spaces (EPVS), which play a significant role in brain fluid exchange and waste removal, may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). In this study, we aimed to explore the shared genetic link and causal effect between EPVS and ALS. Methods: This study used publicly available summary data from the largest and most recent genome-wide association studies (GWAS) on EPVS (n = 40,095) and ALS (n = 138,086) in European populations. EPVS were assessed in the hippocampus (EPVS-HIP), basal ganglia (EPVS-BG), and white matter (EPVS-WM). We used linkage disequilibrium score regression (LDSC) to investigate the genetic correlation. Multi-trait analysis of GWAS (MTAG), Cross-Phenotype Association (CPASSOC) analysis, and genetic colocalization analysis were performed to identify shared risk loci. Bidirectional Mendelian randomization analysis was used to investigate the causal relationship. Results: A negative genetic correlation was observed between EPVS-WM and ALS after Bonferroni correction (rg = -0.24, p < 0.01). No significant correlations were observed between ALS and EPVS-HIP (rg = -0.03, p = 0.79) or EPVS-BG (rg = 0.01, p = 0.91). Four significant loci including rs113247976 in KIF5A and rs118082508 in SDR9C7 were identified as potential pleiotropic loci of the relationship. None of these loci demonstrated evidence of genetic colocalization. Furthermore, Mendelian randomization analysis revealed no causative effect in either direction. Conclusions: EPVS-WM and ALS may share part of their genetic architecture, but no evidence for a causal relationship was observed. Future research is needed to further refine these relationships.

Neuroinflammation is no longer a secondary feature of amyotrophic lateral sclerosis (ALS), but rather a disease-modifying process that actively shapes the motor neuron vulnerability from the earliest stages of pathology. Central and peripheral immune cells, including microglia, astrocytes, and infiltrating T lymphocytes, adopt context-dependent states that can be neuroprotective or neurotoxic depending on disease stage and genetic background. These states are driven by discrete molecular programs, such as cGAS-STING-mediated innate immune sensing, NLRP3 inflammasome activation, and RIPK1-dependent necroptotic signaling, which represent tractable therapeutic targets. The repeated failure of broad-spectrum immunosuppressive trials reflects a fundamental mismatch between the non-selective interventions and the mechanistically distinct immune states of diseases. Converging transcriptomic, genetic, and immunophenotypic evidence supports the existence of putative neuroimmune endotypes in ALS, though this framework remains a working hypothesis pending prospective validation in biomarker-stratified cohorts. Advances in the following three domains are needed for realizing precision immunotherapy: standardized biomarker panels (including cerebrospinal fluid chitinases and TSPO-PET) to stratify patients by inflammatory subtype; pharmacodynamic readouts to confirm target engagement before interpreting clinical outcomes; and adaptive platform trial designs capable of evaluating mechanism-matching interventions in defined subgroups. This review integrates ALS-associated neuroinflammation with emerging precision medicine strategies, arguing that the central translational question is no longer whether or not to target neuroinflammation, but how, when, and in whom neuroinflammation should be targeted.

Amyotrophic lateral sclerosis (ALS) is a heritable disorder where rare variants with low-to-moderate penetrance are thought to dominate genetic risk. To identify such rare variants, we harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases. Rare variant analyses identified several new risk genes, with replication confirming association of YKT6 and supporting HTR3C, GBGT1 and KNTC1. We also provide strong, independent validation for genes with limited previous evidence: ARPP21, DNAJC7 and CFAP410. Notably, in ARPP21, we identified a new high-effect variant (p.P747L) and confirmed that p.P563L is an ALS-associated variant leading to an aggressive disease course. Beyond new discoveries, our analyses largely recapitulated the known genetic architecture of ALS, identifying risk variants in over 20% of cases and supporting a cumulative oligogenic risk model. These findings highlight new translational targets and show that rare variant analyses capture substantially more genetic risk than common variant genome-wide association studies.

Alzheimer's disease(AD),an aging-related disease,is characterized by chronic neuroinflammation and microglial activation,leading to neuronal death.Targeting the NOD-like receptors family pyrin domain containing 3(NLRP3)inflammasome may offer therapeutic benefits.Through extensive screening of a natural herbal library using lipopolysaccharide/nigericin-stimulated BV-2 microglial cells,we discovered that Oenothera biennis,a plant-based functional food,significantly enhanced cell survival and inhibited the NLRP3 inflammasome.This was achieved by downregulating its component proteins and suppressing pyroptosis.Similar protective effects were observed in amyloid β(Aβ)1-42-stimulated BV-2 cells,where O.biennis water extract(OWE)reduced inflammasome activity and modulated microglial phagocytic function.Additionally,OWE protected neuronal PC 12 cells from inflammatory damage,underscoring its neuroprotective potential.Further mechanistic studies revealed that OWE activated autophagy by regulating the AMP-activated protein kinase-phosphoinositide 3-kinase/v-akt murine thymoma viral oncogene homolog/mammalian target of rapamycin(AMPK-PI3K/AKT/mTOR)signaling pathway.The effects of OWE on NLRP3 inflammasome inhibition and pyroptosis were reversed by treatment with bafilomycin A1 and compound C,indicating that autophagy plays a key role in these processes.In vivo studies showed that OWE activated autophagy and ameliorated Aβ-induced paralysis and death in Caenorhabditis elegans.Furthermore,OWE demonstrated neuroprotective effects in 3xTg-AD mice by improving cognitive functions and reducing inflammatory markers through autophagy induction.Collectively,our findings suggest that OWE,as a plant-based functional food,inhibits the activation of the NLRP3 inflammasome in microglia via AMPK-PI3K/AKT/mTOR-mediated autophagy,providing a promising therapeutic avenue for AD.

BackgroundIgG4-related disease (Immunoglobulin G4-related disease) is an immune-mediated condition characterized by elevated serum IgG4 levels, clinically presenting as multi-organ enlargement. However, only case reports exist of IgG4-related disease presenting initially with peripheral neuropathy. This study aims to elucidate the clinical features of IgG4-related disease with prominent peripheral neuropathy manifestations.MethodsWe reviewed 16 cases of IgG4-related disease with peripheral neuropathy as the initial presentation, including 15 cases from the literature and one case from our institution. Patient data were extracted and analyzed, encompassing clinical characteristics, pathological features, electrophysiological findings, and treatment information.ResultsThe median age of onset was 64.5 years, with 3 female and 13 male patients. Initially, 15 patients presented with limb numbness and weakness, while 1 exhibited hoarseness. All 16 patients demonstrated organ enlargement in addition to peripheral nerve damage. Peripheral nerve electrophysiology revealed demyelination and/or axonal lesions. All cases received oral corticosteroids, with immunosuppressants added in 3 cases. All patients responded well to corticosteroid therapy.ConclusionPeripheral neuropathy may present as the initial manifestation of IgG4-related disease. Such neuropathy demonstrates favorable response to corticosteroid therapy, and the indication for adding immunosuppressive agents should be evaluated based on individual circumstances.

OBJECTIVE:Peripheral immunity plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). We previously showed that elevated neutrophil counts are associated with increased risk of ALS occurrence and faster disease progression, potentially through axonal damage. However, the mechanisms linking neutrophils to ALS occurrence remain unclear. Neutrophil-secreted enzymes, key markers of neutrophil activity, may mediate these effects. We therefore investigated the role of neutrophil-secreted enzymes in ALS occurrence. METHODS:Six neutrophil-secreted enzymes were selected from the UK Biobank-Proteomics Platform. Cox proportional hazards regression was used to examine associations between these enzymes and ALS occurrence. Multiple sensitivity analyses were conducted to ensure robustness. Stratified analyses evaluated potential effect modifications by age, sex, and body mass index (BMI). To investigate whether neutrophil-secreted enzymes contribute to ALS occurrence via a "dying-back" mechanism, mediation analysis was performed to assess the indirect effect of neurofilament light chain (NfL) levels in this relationship. RESULTS:Individuals who later developed ALS showed significantly higher levels of neutrophil-secreted enzymes prior to disease onset, suggesting that neutrophil activation occurs before ALS occurrence. Elevated enzyme levels were associated with an increased risk ALS occurrence. Furthermore, we observed a linear positive correlation between enzyme levels and NfL concentrations. Mediation analysis indicated that the effects of MPO and S100A12 on ALS onset were partially mediated through axonal injury. INTERPRETATION:Elevated neutrophil-secreted enzymes are associated with an increased risk of ALS occurrence. This finding provides mechanistic insight into neutrophil involvement in ALS and identifies these enzymes as potential therapeutic targets. ANN NEUROL 2026;99:591-605.

By adopting the method of voxel-mirrored homotopic connectivity (VMHC), the correlation of the synchrony of spontaneous neural functional activities between symmetrical regions is determined to be mediated by the corpus callosum (CC). This study investigated differences in homotopic functional connectivity (FC) across distinct symptom spread directions in individuals with upper motor neuron-dominant amyotrophic lateral sclerosis (UMN-D ALS). The UMN-D ALS patients were categorized into two groups on the basis of the direction of symptom spread—horizontal spread (group H) and vertical spread (group V). Indices of interhemispheric functional and structural changes are derived via analyses of VMHC and probabilistic fiber tracking. The VMHC analysis of grey matter revealed that the intergroup differences in the superior frontal gyrus (SFG) were greater in group H than in groups V and HC (voxel P < 0.05, cluster P < 0.05, GRF corrected). According to CC-based VMHC analysis, group H had greater VMHC values than did group V (45 mm³ vs. 18 mm³ at a voxel-level threshold of P < 0.05, uncorrected). In UMN-D ALS, the results of VMHC analysis vary with different spread directions. In group H, homotopic FC significantly increased, possibly associated with early bilateral limb involvement and subsequent compensatory increases in the SFG. These results contribute to the understanding of the relationship between brain function and symptom evolution in individuals with ALS.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of motor neurons in the brain and spinal cord. It is often associated with specific genetic mutations, such as Sod1 genes. However, the exact mechanism by which Sod1 leads to ALS remains unclear. We used a spatial transcriptomic (ST) technique called Stereo-seq to analyze the molecular changes during the progression of ALS. We observed dysregulated pathways related to RNA and protein synthesis and processing, as well as increased inflammatory signaling in ALS samples. Additionally, in the hypothalamus, showed more serious damage in ALS samples compared to ALS_pre samples, as indicated by the changes in enriched pathways. Our study provides a comprehensive spatially resolved molecular roadmap of ALS mouse model with Sod1 mutation, highlighting the potential of spatial transcriptomics in ALS research.

Introduction:Poor sleep quality affects 50-63% of Amyotrophic lateral sclerosis (ALS) patients, exacerbating disease burden and reducing quality of life. This study aimed to investigate the relationships among disease severity, depressive symptoms, and sleep quality in ALS, with a focus on the mediating effects of depression. Methods:Our study enrolled 408 ALS patients. Disease severity was assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R), sleep quality via the Pittsburgh Sleep Quality Index (PSQI), and psychological status using the Hamilton Depression (HAMD) and Anxiety (HAMA) scales. Statistical analyses included Spearman correlations, multivariate regression, and mediation analysis (Hayes' PROCESS macro). Results:Poor sleep quality (PSQI > 5) was observed in 54.4% of patients. Multivariate analysis found ALSFRS-R (β = -0.135, p = 0.042) and HAMD (β = 0.270, p < 0.001) correlated with sleep quality. Initial mediation analysis using the full ALSFRS-R and PSQI scales was not significant. Aimed to further explore the correlation, we derived specific subscales ALSFRS-R' (motor/respiratory components) and PSQI' (sleep efficiency/ daytime dysfunction), which more correlated with each other. Mediation analysis of these subscales revealed that depressive symptoms accounted for 36.3% of the indirect effect between ALSFRS-R' and PSQI'. Discussion:Our cross-sectional exploratory study suggests that depression may partly mediate the relationship between motor dysfunction and poor sleep quality in patients with ALS. Although our mediation analysis suggested a potential association, further longitudinal cohort studies are needed to confirm these findings. The potential mediating role of depression underscores the need for an integrated clinical management approach addressing not only motor symptoms but psychological well-being as well.

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited peripheral neuropathy and currently lacks disease-modifying therapy. PXT3003, a low-dose oral combination targeting PMP22 overexpression, has shown efficacy in two trials, while one recent confirmatory trial failed to meet its primary efficacy endpoints. In this trial, eligible participants aged 16 to 65 years with genetically confirmed mild-to-moderate CMT1A were randomly assigned to receive oral PXT3003 or placebo twice daily for 15 months. The primary endpoint was the change in the overall neuropathy limitations scale (ONLS) total score from baseline to month 15. At month 15, mean ONLS change from baseline was -0.268 (SD: 0.82) in the PXT3003 group versus 0.013 (SD: 0.65) in the placebo group, with a between-group difference of -0.249 (95% confidence interval [CI]: -0.467 to -0.030; p = 0.0257). Significant improvements were observed in the ONLS leg subscore and ankle-dorsiflexion strength. These findings support PXT3003 as a promising therapeutic option for alleviating limb symptoms in patients with CMT1A.

In human disease, clinical manifestations are not always tightly correlated with genetic etiology. While the GGGGCC (G4C2) hexanucleotide repeat expansion in the C9orf72 gene is the most prevalent genetic cause of ALS, a subset of mutation carriers stays asymptomatic. The molecular mechanisms underlying this incomplete penetrance remain elusive. Here, we identify L-azetidine-2-carboxylic acid (AZE), a dietary non-protein amino acid, as a critical environmental risk factor capable of unmasking latent genetic susceptibility in C9orf72-ALS pathogenesis. Specifically, AZE disrupts the proteasome-mediated clearance of toxic poly-GA dipeptide repeats derived from G4C2 repeats, triggering pronounced neuroinflammation and motor defects in a C9orf72-ALS mouse model that otherwise exhibits minimal phenotypes. Notably, AZE is widely present in the food chain (particularly in sugar beet) and consistently detectable in the postmortem human brains. A significant positive correlation was observed between sugar beet consumption and the incidence of sporadic C9-ALS cases in European nations. Critically, dietary intake of sugar beet juice is sufficient to activate subclinical genetic susceptibility in C9orf72-ALS mice. These findings reveal a direct diet-gene interplay in governing C9orf72-ALS penetrance, and propose dietary restriction of AZE-rich foods as a tangible strategy for genetically susceptible individuals to potentially delay or mitigate this currently incurable disorder. ### Competing Interest Statement The authors have declared no competing interest. National Key R&D Program of China, 2025YFC3409700 STI2030-Major Projects, 2021ZD0202501 National Natural Science Foundation of China, 82325016, 82150003, 32421001, 32400780, 32300790

TAR DNA-binding protein (TDP-43) is a multifunctional protein that binds DNA and RNA within the nucleus. In neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS), TDP-43 is mislocalized to the cytoplasm, forming inclusions. Current TDP-43 transgenic mouse models generally fail to exhibit significant cytoplasmic accumulation and loss of nuclear TDP-43, which hampers the investigation of cytoplasmic TDP-43 pathology. We previously discovered that primate-specific caspase-4 (CASP4) can cleave TDP-43, producing truncated fragments that are mislocalized to the cytoplasm. Here we show that a transgenic mouse model that expresses human CASP4 and recapitulates the cytoplasmic mislocalization of endogenous TDP-43 and motor dysfunction in an age-dependent manner. Moreover, CASP4 mice exhibited gene expression changes and neuropathology similar to patients with sporadic ALS. Inhibition of CASP4 by its antisense oligonucleotide ameliorated TDP-43 pathology and subsequent neurotoxicity in CASP4 mice. Thus, CASP4 mice present a valuable animal model for exploring endogenous TDP-43-mediated pathogenesis and therapeutics.