Amyotrophic Lateral Sclerosis Research

Cell-Type Specific Molecular and Functional Consequences of TDP-43 Loss-of-Function in Human Induced Neurons

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.

RIG-I mediated neuron-specific IFN type 1 signaling in FUS-ALS induces neurodegeneration and offers new biomarker-driven individualized treatment options for (FUS-)ALS

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.

Pathological TDP-43 filaments accumulate at synapses and cause synaptic dysfunction

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

STMN2 protein depletion via translation deficits and stress granules and its compensation in ALS

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.

Droplet growth, Ostwald's rule, and emergence of order in Fused in Sarcoma

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.

Deletion of the Saccharomyces cerevisiae RACK1 homolog, ASC1, enhances autophagy and counteracts TDP-43 toxicity

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.

Differential TDP-43 interactomes between the cortex and cerebellum in the mouse

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

Dietary Non-protein Amino Acid AZE as an Environmental Trigger Activating Latent Genetic Susceptibility in C9orf72-ALS Pathogenesis

Distinct TAF15 amyloid filament folds define multiple subtypes of FTLD-TAF15

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

TDP-43 dysfunction leads to the accumulation of cryptic transposable element-derived exons, crypTEs, in iPSC derived neurons and ALS/FTD patient tissues

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.

Identification of molecular and clinical ALS subgroups based on TDP-43 loss of function molecular markers from population-based patient-derived iPS motor neurons

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.

Divergent TDP43-regulated and TDP43-independent cryptic splicing in the cortex and spinal cord

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

Metabolic alterations in the absence of a detectable neuromuscular phenotype in novel genomically humanised SOD1A4V mice.

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.

Amygdala TDP-43 pathology is associated with behavioural dysfunction and ferritin accumulation in amyotrophic lateral sclerosis.

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

Microscale dysfunction and mesoscale compensation in degenerating neuronal networks

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.

A mouse model of CHCHD10 p.R15L familial ALS presents mild, age-related motor neuron degeneration without protein instability or mitochondrial dysfunction

Lysosomal escape and TMEM106B fibrillar core determine TDP-43 seeding outcomes

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

Non-linear gene sets for digital biomarkers of amyotrophic lateral sclerosis

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.

Progressive muscle metabolic reprogramming in asymptomatic ALS gene mutation carriers

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

Elevated neuronal TAF15 expression leads to FTD-like phenotype

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

Site-specific methionine oxidation alters structure and phase separation of TDP-43 C-terminal domain

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

3' UTR variants of ALS-linked RNAs modify subcellular and cellular phenotypes

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

Regulation of Glypican 6-mediated Wnt activation maintains TDP-43 nuclear localization in neurons

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

Ubiquitin Proteasome System Components, RAD23A and USP13, Modulate TDP-43 Solubility and Neuronal Toxicity

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

ALS/FTD-associated TDP-43 mutations promote fragility of genes governing excitatory neurotransmission via topoisomerase IIβ impairment

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

Dual-targeting snRNA gene therapy rescues STMN2 and UNC13A splicing in TDP-43 proteinopathies

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.

Human TDP-43 overexpression in zebrafish motor neurons triggers MND-like phenotypes through gain-of-function mechanism

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.

Progranulin loss induces mitochondrial dysfunction and ferroptosis in human cerebral organoids

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

Structural details of helix-mediated TDP-43 C-terminal domain multimerization

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.

Mutant FUS perturbs m6A regulation by repressing ALKBH5, while restoring m6A levels alleviates ALS pathology in vivo

This study shows that mutant FUS reduces ALKBH5 expression, increasing m6A levels, and that restoring m6A alleviates ALS pathology in Drosophila models.