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Mutations in the TARDBP gene, which encodes the TDP-43 protein, account for only 3–5% of familial cases of amyotrophic lateral sclerosis and less than 1% of cases that are apparently idiopathic. However, the discovery of neuronal inclusions of TDP-43 as the neuropathological hallmark in the majority of cases of amyotrophic lateral sclerosis has transformed our understanding of the pathomechanisms underlying neurodegeneration. An individual TARDBP mutation can cause phenotypic heterogeneity. Most mutations lie within the C-terminus of the TDP-43 protein. In pathological conditions, TDP-43 is mislocalised from the nucleus to the cytoplasm, where it can be phosphorylated, cleaved, and form insoluble aggregates. This mislocalisation leads to dysfunction of downstream pathways of RNA metabolism, proteostasis, mitochondrial function, oxidative stress, axonal transport, and local translation. Biomarkers for TDP-43 dysfunction and targeted therapies are being developed, justifying cautious optimism for personalised medicine approaches that could rescue the downstream effects of TDP-43 pathology.

Axonal dysfunction is a common phenotype in neurodegenerative disorders, including in amyotrophic lateral sclerosis (ALS), where the key pathological cell-type, the motor neuron (MN), has an axon extending up to a metre long. The maintenance of axonal function is a highly energy-demanding process, raising the question of whether MN cellular energetics is perturbed in ALS, and whether its recovery promotes axonal rescue. To address this, we undertook cellular and molecular interrogation of multiple patient-derived induced pluripotent stem cell lines and patient autopsy samples harbouring the most common ALS causing mutation, C9orf72. Using paired mutant and isogenic expansion-corrected controls, we show that C9orf72 MNs have shorter axons, impaired fast axonal transport of mitochondrial cargo, and altered mitochondrial bioenergetic function. RNAseq revealed reduced gene expression of mitochondrially encoded electron transport chain transcripts, with neuropathological analysis of C9orf72-ALS post-mortem tissue importantly confirming selective dysregulation of the mitochondrially encoded transcripts in ventral horn spinal MNs, but not in corresponding dorsal horn sensory neurons, with findings reflected at the protein level. Mitochondrial DNA copy number was unaltered, both in vitro and in human post-mortem tissue. Genetic manipulation of mitochondrial biogenesis in C9orf72 MNs corrected the bioenergetic deficit and also rescued the axonal length and transport phenotypes. Collectively, our data show that loss of mitochondrial function is a key mediator of axonal dysfunction in C9orf72-ALS, and that boosting MN bioenergetics is sufficient to restore axonal homeostasis, opening new potential therapeutic strategies for ALS that target mitochondrial function.

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease marked by motor deterioration and cognitive decline. Early diagnosis is challenging due to the complexity of sporadic ALS and the lack of a defined risk population. In this study, we developed Miniset-DenseSENet, a convolutional neural network combining DenseNet121 with a Squeeze-and-Excitation attention mechanism, using 190 autopsy brain images from the Gregory Laboratory at the University of Aberdeen. The model distinguishes controls, ALS patients with no cognitive impairment, and ALS patients with cognitive impairment (ALS-frontotemporal dementia) with 97.37% accuracy, addressing a significant challenge in overlapping neurodegenerative disorders involving TDP-43 proteinopathy. Miniset-DenseSENet outperformed other transfer learning models, achieving a sensitivity of 1 and specificity of 0.95. These findings suggest that integrating transfer learning and attention mechanisms into neuroimaging can enhance diagnostic accuracy, enabling earlier ALS detection and improving patient stratification. This model has the potential to guide clinical decisions and support personalied therapeutic strategies.

Many genes have been linked to amyotrophic lateral sclerosis (ALS), including never in mitosis A (NIMA)‐related kinase 1 (NEK1), a serine/threonine kinase that plays a key role in several cellular functions, such as DNA damage response and cell cycle regulation. Whole‐exome sequencing studies have shown that NEK1 mutations are associated with an increased risk for ALS, where a significant enrichment of NEK1 loss‐of‐function (LOF) variants were found in individuals with ALS compared to controls. In particular, the p.Arg261His missense variant was associated with significantly increased disease susceptibility. This case series aims to understand the neuropathological phenotypes resulting from NEK1 mutations in ALS. We examined a cohort of three Scottish patients with a mutation in the NEK1 gene and evaluated the distribution and cellular expression of NEK1, as well as the abundance of phosphorylated TDP‐43 (pTDP‐43) aggregates, in the motor cortex compared to age‐ and sex‐matched control tissue. We show pathological, cytoplasmic TDP‐43 aggregates in all three NEK1‐ALS cases. NEK1 protein staining revealed no immunoreactivity in two of the NEK1‐ALS cases, indicating a LOF and corresponding to a reduction in NEK1 mRNA as detected by in situ hybridisation. However, the p.Arg261His missense mutation resulted in an increase in NEK1 mRNA molecules and abundant NEK1‐positive cytoplasmic aggregates, with the same morphologic appearance, and within the same cells as co‐occurring TDP‐43 aggregates. Here we show the first neuropathological assessment of a series of ALS cases carrying mutations in the NEK1 gene. Specifically, we show that TDP‐43 pathology is present in these cases and that potential NEK1 LOF can either be mediated through loss of NEK1 translation or through aggregation of NEK1 protein as in the case with p.Arg261His mutation, a potential novel pathological feature of NEK1‐ALS. Illustration of the structural and functional consequences of ALS‐associated NEK1 mutations in our cohort.

Nuclear clearance and cytoplasmic aggregation of TDP-43, initially identified in ALS-FTD, are hallmark pathological features observed across a spectrum of neurodegenerative diseases. We previously found that TDP-43 loss-of-function leads to transcriptome-wide inclusion of deleterious cryptic exons, a signature detected in presymptomatic biofluids and postmortem ALS-FTD brain tissue, but the upstream mechanisms that lead to TDP-43 dysregulation remain unclear. Here, we developed a web-based resource (SnapMine) to determine the levels of TDP-43 cryptic exon inclusion across hundreds of thousands of publicly available RNA sequencing datasets. We established cryptic exon inclusion levels across a variety of human cells and tissues to provide ground truth references for future studies on TDP-43 dysregulation. We then explored studies that were entirely unrelated to TDP-43 or neurodegeneration and found that ciclopirox olamine (CPX), an FDA-approved antifungal, can trigger the inclusion of TDP-43-associated cryptic exons in a variety of mouse and human primary cells. CPX induction of cryptic exons arises from heavy metal toxicity and oxidative stress, suggesting that similar vulnerabilities could play a role in neurodegeneration. Our work demonstrates how diverse datasets can be linked through common biological features and underscores how public archives of sequencing data remain a vastly underutilized resource with tremendous potential for uncovering novel insights into complex biological mechanisms and diseases. TDP-43 nuclear clearance and loss-of-function, a hallmark of ALS-FTD and other neurodegenerative diseases, causes widespread inclusion of harmful cryptic exons. Here, the authors developed SnapMine to analyze cryptic exon inclusion across public RNA-seq datasets and identified that the antifungal ciclopirox olamine (CPX) induces such inclusion via heavy metal toxicity and oxidative stress.

An international expert panel convened to evaluate nutrition-based approaches to brain health and dementia prevention. This consensus statement integrates perspectives from lived experiences, mechanistic evidence, epidemiology, and clinical interventions. Nutrition plays a crucial role in brain health throughout life and in cognitive decline pathogenesis, particularly through the food-gut-brain axis. Intervention effectiveness varies across the health promotion, prevention, treatment, and maintenance spectrum due to methodological differences and individual responses to nutritional interventions. The Mediterranean and MIND dietary patterns show promise for maintaining cognitive function across studies. Multi-domain interventions like FINGER effectively combine dietary modifications with lifestyle changes to delay dementia onset in at-risk older adults. These findings align with mechanistic evidence on the food-gut-brain axis in maintaining optimal brain health by preventing neurodegeneration. Key mechanisms include gut microbiota composition and function, blood-brain barrier integrity, endothelial and mitochondrial dysfunction, insulin resistance, oxidative stress, and inflammatory processes. Research priorities include standardizing cognitive assessment methodologies, developing early intervention strategies, and implementing integrated precision nutrition and lifestyle approaches. Incorporating patients’ and caregivers’ lived experiences in research co-production was identified as essential to support those with lived experience. The panel concluded that future directions should combine population and individual-level preventive approaches while addressing challenges in sustaining healthy behavioral changes and understanding the complex interplay between diet, lifestyle, and genetic factors in brain health and dementia prevention. Experts emphasized the need for both standardized methodologies and personalized interventions to account for individual variability in nutritional responses and facilitate effective prevention strategies across diverse populations.

IntroductionMotor neuron disease (MND) is a rapidly fatal neurodegenerative disease. Despite decades of research and clinical trials there remains no cure and only one globally approved drug, riluzole, which prolongs survival by 2–3 months. Recent improved mechanistic understanding of MND heralds a new translational era with many potential targets being identified that are ripe for clinical trials. Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART) aims to evaluate the efficacy of drugs efficiently and definitively in a multi-arm, multi-stage, adaptive trial. The first two drugs selected for evaluation in MND-SMART are trazodone and memantine.Methods and analysisInitially, up to 531 participants (177/arm) will be randomised 1:1:1 to oral liquid trazodone, memantine and placebo. The coprimary outcome measures are the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) and survival. Comparisons will be conducted in four stages. The decision to continue randomising to arms after each stage will be made by the Trial Steering Committee who receive recommendations from the Independent Data Monitoring Committee. The primary analysis of ALSFRS-R will be conducted when 150 participants/arm, excluding long survivors, have completed 18 months of treatment; if positive the survival effect will be inferentially analysed when 113 deaths have been observed in the placebo group. The trial design ensures that other promising drugs can be added for evaluation in planned trial adaptations. Using this novel trial design reduces time, cost and number of participants required to definitively (phase III) evaluate drugs and reduces exposure of participants to potentially ineffective treatments.Ethics and disseminationMND-SMART was approved by the West of Scotland Research Ethics Committee on 2 October 2019. (REC reference: 19/WS/0123) Results of the study will be submitted for publication in a peer-reviewed journal and a summary provided to participants.Trial registration numbersEuropean Clinical Trials Registry (2019-000099-41); NCT04302870.

Background Amyotrophic lateral sclerosis (ALS) is a rapidly progressive fatal neurodegenerative condition. There are no effective treatments. The only globally licensed medication, that prolongs life by 2-3 months, was approved by the FDA in 1995. One reason for the absence of effective treatments is disease heterogeneity noting that ALS is clinically heterogeneous and can be considered to exist on a neuropathological spectrum with frontotemporal dementia. Despite this significant clinical heterogeneity, protein misfolding has been identified as a unifying pathological feature in these cases. Based on this shared pathophysiology, we carried out a systematic review and meta-analysis to assess the therapeutic efficacy of compounds that specifically target protein misfolding in preclinical studies of both ALS and FTD. Methods Three databases: (i) Pubmed, (ii) MEDLINE and (iii) EMBASE were searched. All studies comparing the effect of treatments targeting protein misfolding in pre-clinical ALS or FTD models to a control group were retrieved. Results Systematic review identified 70 pre-clinical studies investigating the effects of therapies targeting protein misfolding on survival. Meta-analysis revealed that targeting protein misfolding did significantly improve survival compared to untreated controls (p<0.001, (df)=68, = 0.05, (CI) 1.05-1.16), with no evidence of heterogeneity between studies (I2= 0%). Further subgroup analyses, evaluating the effect of timing of these interventions, showed that, only treating prior to symptom onset (n=33), significantly improved survival (P<0.001, df=31, = 0.05, (CI) 1.08-1.29), although this likely reflects the inadequate sample size of later time points. Furthermore, arimoclomol was found to significantly reduce secondary outcome measures including: (i) histological outcomes, (ii) behavioural outcomes and (iii) biochemical outcomes (p<0.005). Conclusions This analysis supports the hypothesis that protein misfolding plays an important role in the pathogenesis of ALS and FTD and that targeting protein misfolding, at least in pre-clinical models, can significantly improve survival, especially if such an intervention is administered prior to symptom onset.

Abnormal aggregation of TAR DNA‐binding protein 43 (TDP‐43) is a pathological hallmark of motor neuron disease (MND), yet current methods for quantifying these aggregates in biological samples remain limited in sensitivity and resolution. Here, single‐molecule fluorescence microscopy is applied to post‐mortem brain extracts to quantitatively characterize aggregates containing TDP‐43 at the individual particle level. The resulting aggregate fingerprints, consisting of morphological and compositional profiles, are sufficient to distinguish MND donors from neurologically normal controls and further discriminate between clinically distinct MND subgroups. Comparative proteomic analysis confirms and extends these findings, revealing convergent and complementary molecular signatures. These results demonstrate, for the first time, that single‐molecule aggregate profiling can stratify MND cases using patient‐derived tissues, paving the way for the development of sensitive minimally invasive diagnostics and mechanistically informed disease monitoring tools. Single‐molecule fluorescence microscopy is combined with proteomic profiling to fingerprint the morphology and composition of TDP‐43 protein aggregates found in post‐mortem motor neuron disease brain tissues. Aggregate fingerprints can distinguish disease from control donors and detect unexpected TDP‐43 pathology in SOD1‐MND. These findings challenge existing models and offer a new route toward sensitive diagnostics and patient stratification tools.

Almost all cases of sporadic amyotrophic lateral sclerosis (ALS), and some cases of the familial form, are characterised by the deposition of TDP-43, a member of a family of heteronuclear ribonucleoproteins (hnRNP). Although protein misfolding and deposition is thought to be a causative feature of many of the most prevalent neurodegenerative diseases, a link between TDP-43 aggregation and the dysfunction of motor neurons has yet to be established, despite many correlative neuropathological studies. We have investigated this relationship in the present study by probing the effect of altering TDP-43 aggregation behaviour in vivo by modulating the levels of molecular chaperones in a Drosophila model. More specifically, we quantify the effect of either pharmacological upregulation of the heat shock response or specific genetic upregulation of a small heat shock protein, CG14207, on the neurotoxicity of both TDP-43 and of its disease associated 25 kDa fragment (TDP-25) in a Drosophila model. Inhibition of the aggregation of TDP-43 by either method results in a partial reduction of its neurotoxic effects on both photoreceptor and motor neurons, whereas inhibition of the aggregation of TDP-25 results not only in a complete suppression of its toxicity but also its clearance from the brain in both neuronal subtypes studied. The results demonstrate, therefore, that aggregation plays a crucial role in mediating the neurotoxic effects of both full length and truncated TDP-43, and furthermore reveal that the in vivo propensity of these two proteins to aggregate and their susceptibility to molecular chaperone mediated clearance are quite distinct.