Amyotrophic Lateral Sclerosis Research

This study shows that cortical hyperexcitability in mice leads to ALS-like motor symptoms and pathology through a dying-forward mechanism.

The paper uses molecular dynamics simulation and machine learning to analyze disease-associated mutations in TDP-43 and identifies structural features linked to protein stability and pathogenesis.

The paper creates genomically humanised knock-in mice for ALS/FTD genes SOD1, TARDBP, and FUS, showing they express human proteins at endogenous levels and are phenotypically normal.

This paper demonstrates that a cyclic thiosulfinate cross-linker stabilizes SOD1 variants in vivo, showing efficacy and low toxicity for treating SOD1-related ALS.

The paper investigates how N-terminal phosphorylation of FUS affects its protein interactome using proximity labeling and mass spectrometry, revealing distinct interactome changes and functional consequences.

The paper identifies non-coding variants in the IL18RAP 3'UTR that reduce ALS risk by modulating neuro-inflammation through NF-κB signaling in microglia.

The paper shows that Caspar overexpression in glia slows ALS progression by reducing inflammation in a Drosophila model.

The paper shows that ALS/FTD risk variants in UNC13A increase sensitivity to TDP-43 depletion by promoting cryptic exon inclusion and protein loss.

This study shows that dipeptide repeat proteins from C9ORF72 mutations disrupt GEM body formation and cause SMN protein mislocalization in motor neurons.

This study identifies TDP-25 inclusions as sequestering proteasomes, leading to proteostasis impairment in ALS/FTD.

The paper uses single cell transcriptomics to identify master regulators of dysfunctional pathways in SOD1 ALS motor neurons, finding SMAD2 activation as a key driver of neurodegeneration.

This study examines the effect of ozone exposure on ALS pathology in a TDP-43A315T mice model, finding altered metabolic profiles and potential improvements in motor performance.

This paper demonstrates that TDP-43 paralogs in the killifish N. furzeri form amyloid-like aggregates during ageing, suggesting the fish as a model for TDP-43-related neurodegenerative diseases.

This study shows that inhibiting GSK3 reduces TDP-43 levels and neurotoxicity in mammalian neurons by promoting TDP-43 turnover through a caspase-dependent mechanism.

The paper identifies cytoplasmic intron-retaining transcripts (IRTs) associated with miRNA activity changes in ALS, showing VCP mutations increase IR and target gene expression.

This study shows SRCP1 reduces insoluble SOD1 in ALS models but does not extend mouse lifespan.

This study investigates how mutations in axonal transport genes modify neuromuscular defects in Drosophila SOD1 mutants, revealing isoform-specific effects on survival and junction morphology.

The paper performs an integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients to identify dysregulated pathways and validate them in vivo and in postmortem data.

This study shows TDP-43 stabilizes G3BP1 transcripts via direct binding, and TDP-43 depletion reduces G3BP1 protein levels, contributing to stress granule dysfunction in ALS/FTD.

This study examines C9orf72 ALS/FTD patient-derived iPSC-microglia mono-cultures, finding they form RNA foci, have reduced C9orf72 protein, and show endosomal-lysosomal dysfunction, but no significant microglial-enriched gene expression differences.

This study shows that ALS-FUS mutations disrupt HuD/ELAVL4 and FMRP activities, leading to axon phenotypes in motoneurons through altered transcript stability.

The paper identifies aberrant cytoplasmic intron-retaining transcripts (IRTs) in ALS and shows their association with RBP mislocalization.

The paper quantifies the caudal-rostral progression of alpha motoneurone degeneration in SOD1G93A mice, showing greater susceptibility in lumbar spinal cord regions.

This study shows that synaptic accumulation of FUS in ALS-FUS mice leads to age-dependent misregulation of inhibitory synapses, suggesting a role in early neurodegeneration.

This paper presents the cryoEM structure of hnRNPA2 LCD fibrils, showing structural differences from pathogenic amyloid and how mutations convert it to a pathogenic form.

This study shows CDNF reduces ER stress and improves motor neuron survival in multiple ALS models, independent of genetic cause.

The paper identifies cyclin F interactors using BioID and shows that ALS/FTD-associated cyclin F mutations disrupt paraspeckle protein homeostasis, particularly RBM14 levels in patient tissue.

This study identifies circulating protein aggregates as a source of ALS biomarkers and therapeutic targets by showing their enrichment with brain proteins and pathological features.

This study shows that C9ORF72 ALS pathogenesis involves both gain and loss of function mechanisms causing axonal organelle trafficking impairment and DNA damage.