Amyotrophic Lateral Sclerosis Research

The paper identifies divergent mitochondrial and metabolic profiles between ALS-vulnerable and resilient neurons, revealing how these differences contribute to selective vulnerability in ALS.

This study examines the molecular and functional effects of TDP-43 loss in human induced neurons, revealing cell-type-specific gene expression and splicing changes, and a hyperexcitable phenotype in both glutamatergic and cholinergic motor neurons.

The paper identifies RIG-I-mediated innate immune activation in FUS-ALS spinal motor neurons due to mitochondrial dsRNA accumulation, which can be targeted by JAK-STAT inhibition, offering potential biomarker-driven treatment options.

This study shows TDP-43 filaments accumulate at synapses, causing presynaptic dysfunction and neuronal hyperexcitability in neurodegenerative diseases.

This study identifies TDP-43-independent mechanisms of STMN2 depletion in ALS, showing acute stress causes proteasomal degradation and translational repression, while chronic stress leads to reduced protein levels, with mRNA upregulation as a compensatory mechanism in some subtypes.

This study investigates the phase separation and assembly of FUS-LC, showing that core regions form in a specific order and that Ostwald's rule applies to their maturation and stability.

This paper shows that deleting ASC1 in yeast reduces TDP-43 toxicity by enhancing autophagy, rather than through polysome sequestration, while FUS toxicity remains unaffected.

The paper identifies differences in TDP-43 interactomes between the cortex and cerebellum in healthy mice, suggesting regional vulnerability to TDP-43 aggregation.

This study identifies distinct TAF15 amyloid filament structures in different FTLD-FET subtypes, leading to the renaming of the disease group as FTLD-TAF15.

This study identifies TDP-43-dependent cryptic gene-TE fusions (crypTEs) in neurons and ALS/FTD tissues, showing their association with altered gene expression and potential pathogenic effects.

The paper identifies molecular and clinical subgroups of ALS using TDP-43 loss-of-function markers from patient-derived iPS motor neurons, revealing distinct disease severity and clinical outcomes.

The paper identifies 142 cryptic splices in ALS and FTD tissues, revealing divergent splicing between spinal cord and cortex, and highlights TDP43-independent events.

This study generates and analyzes a novel genomically humanised SOD1A4V mouse model, revealing metabolic dysfunction through multi-omic analyses and identifying it as a potential pre-symptomatic ALS model.

The paper shows that amygdala TDP-43 pathology correlates with behavioural dysfunction and ferritin accumulation in sporadic ALS.

This study investigates microscale and mesoscale changes in ALS motor neuron networks using in vitro models, showing increased network centralisation and rich-club connectivity as compensatory mechanisms.

The paper investigates factors determining TDP-43 seeding outcomes in FTLD-TDP, identifying TMEM106B fibrillar core and lysosomal escape as critical drivers.

The paper identifies non-linear gene sets from blood cells to classify ALS with high accuracy using machine learning and validates findings in lab samples and iPSC-derived motor neurons.

Skeletal muscle from individuals at elevated genetic risk for ALS/FTD undergoes progressive metabolic reprogramming far before disease onset.

This study shows that elevated TAF15 expression in neurons causes oxidative stress, neurotoxicity, and FTD-like behaviors, which can be reversed by antioxidants.

This study shows methionine oxidation in TDP-43's C-terminal domain disrupts structure and phase separation through region-specific mechanisms.

The paper investigates how 3' UTR variants of ALS-linked RNAs affect cell morphology and function in neuronal cells.

This study identifies a signaling axis involving GDE2, GPC6, and the Wnt pathway that regulates NPC integrity and TDP-43 nuclear localization in neurons.

This study identifies RAD23A and USP13 as modifier genes that enhance TDP-43 solubility and reduce neuronal toxicity in ALS models.

This paper shows that ALS/FTD-linked TDP-43 mutations cause DNA breaks in genes controlling excitatory neurotransmission by impairing topoisomerase IIβ function.

This study develops a gene therapy strategy using snRNAs to correct mis-splicing of STMN2 and UNC13A in TDP-43 proteinopathies, showing restoration of protein levels and axonal regeneration in motor neurons.

This study uses zebrafish models to show that human TDP-43 overexpression in motor neurons causes MND-like phenotypes through gain-of-function mechanisms, with distinct effects based on TDP-43 variant.

This study shows that PGRN loss in human cerebral organoids causes mitochondrial dysfunction and ferroptosis through oxidative stress and iron accumulation.

This study investigates the structural basis of TDP-43 C-terminal domain multimerization using biophysical experiments, AlphaFold2-Multimer, and simulations, revealing helical oligomerization and the role of specific residues in phase separation and disease.