Amyotrophic Lateral Sclerosis Research

U7 small nuclear RNA splice-switching therapeutics for STMN2 and UNC13A in Amyotrophic Lateral Sclerosis

The paper develops U7 snRNA therapeutics to correct TDP-43-dependent mis-splicing in ALS, restoring gene expression and neuronal function in human iPSC-derived neurons.

The molecular mechanism of uptake and cell-to-cell transmission of arginine-containing dipeptide repeat proteins.

This paper identifies CSPG4 as a mediator of arginine-rich DPR uptake and cell-to-cell transmission, suggesting it as a therapeutic target for ALS/FTD.

Ataxin-2 Coordinates Neuronal and Glial Pathways to Promote Neuroprotection

This study identifies how ataxin-2 reduction promotes neuroprotection by activating metabolic programs in neurons and astrocytes, enhancing energy production and trophic support.

Sensitivity to TDP-43 loss and degradation resistance determine cryptic exon biomarker potential

The paper identifies cryptic splicing events (CEs) sensitive to TDP-43 loss and develops a composite score to detect TDP-43 pathology across tissues.

TDP-43 suppression of ATP8A2 cryptic splicing implicates phosphatidylserine-driven neuroinflammation in ALS/FTD

This study identifies ATP8A2 as a TDP-43 target whose loss leads to PS exposure and neuroinflammation, suggesting immune cell inhibition as a therapeutic strategy for ALS-FTD and CAMRQ4.

Investigation of mitochondrial phenotypes in motor neurons derived by direct conversion of fibroblasts from familial ALS subjects

This study investigates mitochondrial phenotypes in motor neurons derived from familial ALS patients using direct conversion of fibroblasts, identifying metabolic and functional differences across mutations.

A validated panel of commercial antibodies for reliable detection of FET proteins.

The paper evaluates 23 commercial antibodies for detecting FET proteins, identifies specific ones, and provides a validated panel for reliable research.

Mislocalisation of TDP-43 to the cytoplasm of either neurons or oligodendrocytes causes axonopathy and dysmyelination

This study shows that mislocalisation of TDP-43 to the cytoplasm in neurons or oligodendrocytes causes axonopathy and dysmyelination, highlighting the role of cell-type-specific loss of function in neurodegeneration.

The structure, redox chemistry and motor neuron toxicity of heterodimeric zinc-deficient SOD1-Implications for the toxic gain of function observed in ALS.

This study shows that zinc-deficient SOD1 forms toxic heterodimers with wild-type SOD1, contributing to ALS pathology through enhanced redox activity and motor neuron toxicity.

Nuclear-import receptors remodel the dilute phase to suppress phase transitions of RNA-binding proteins with prion-like domains.

This study shows nuclear-import receptors suppress RNA-binding protein phase transitions by remodeling the dilute phase, preventing disease-linked aggregation.

Elucidating the conformational dynamics of the mitochondrial localization signal, M3, of TDP-43 and accessing potential inhibitors using molecular docking and simulation

This study identifies vitamin D3 as a potential inhibitor of TDP-43's mitochondrial mis-localization through molecular docking and simulation of the M3 region.

CRISPR/Cas9-mediated generation of a de novo C9ORF72 knock-in isogenic iPSC cell bank to model ALS and FTD

The paper generates isogenic iPSC lines with a C9ORF72 G4C2 repeat expansion to model ALS and FTD, showing both loss- and gain-of-function pathologies.

Export-biased, 3'UTR-preserving TDP-43 model links nuclear loss to cytoplasmic aggregation in ALS/FTLD

This study shows that export-biased TDP-43 with intact 3' UTR leads to cytoplasmic aggregation and splicing defects, even when exogenous levels match endogenous, suggesting loss of nuclear function.

Expanding the spectrum of annexin A11 proteinopathy in frontotemporal lobar degeneration and motor neuron disease

The paper characterizes ANXA11 proteinopathy in FTLD-PLS and MND-TDP cases, showing it is common in FTLD-PLS but not linked to pathogenic ANXA11 variants or TDP type C.

Phase Behavior of TDP-43 and hnRNP H1: From Soluble and Aggregated States to Liquid-Like Droplets

This study investigates the phase behavior of TDP-43 and hnRNP H1, revealing an aggregate-to-droplet transition and domain matching in phase separation of LCD-containing proteins.

PIAS1/PIAS4-Mediated SUMOylation of TDP-43 is Induced by Oxidative Stress

The paper investigates TDP-43 SUMOylation and its role in DNA damage repair under oxidative stress.

An ALS-associated TARDBP mutation drives cryptic exon inclusion and RNA dysregulation

Human brain organoids show that a TDP-43 mutation causes RNA mis-splicing and neuronal stress in ALS.

Synaptopathy in the TDP43ΔNLS Mouse Model of Sporadic Amyotrophic Lateral Sclerosis

This study identifies synapse-specific pathology in a TDP43 mouse model of ALS, showing changes in cholinergic and excitatory synapses but not astrocytic pathology.

KIF5A binds RNA to orchestrate synaptic mRNA localization and stress granules in ALS

This study shows KIF5A binds RNA to regulate synaptic mRNA localization and stress granules, with ALS mutations disrupting synaptic homeostasis.

A non-human primate model of Amyotrophic Lateral Sclerosis

This study overexpresses TDP-43 in rhesus macaques to create an ALS model, showing motor neuron degeneration and widespread TDP-43 pathology.

Loss of FXR1 and FXR2 promotes accumulation of TDP-43 in aging-related stress granules

The paper shows that loss of FXR1 and FXR2 leads to TDP-43 accumulation in stress granules, linking FXP family reduction to neurodegenerative pathology.

TDP-43 dysfunction leads to impaired proteostasis and predisposes mice to worse neurological outcomes after brain injury

This study shows that TDP-43 dysfunction impairs proteostasis and worsens neurological outcomes after brain injury in mice.

MRI-based classifier to identify close-to-onset cases in C9orf72 genetic frontotemporal dementia

The paper develops an MRI-based machine learning classifier to identify presymptomatic C9orf72 carriers at high risk of disease onset within two years.

The effect of aging on post-translational modifications of wild-type human SOD1 and the A5V ALS mutant

This study examines how aging affects post-translational modifications (PTMs) of wild-type and A5V ALS mutant human SOD1, revealing age-related changes in oxidation, formylation, and carboxylation.

Aberrant NSUN1 Activity Connects m5C RNA Modification to TDP-43 Neurotoxicity in ALS/FTD

This study identifies NSUN1-mediated m5C RNA methylation as a driver of TDP-43 cytoplasmic accumulation and neurotoxicity in ALS/FTD.

Preemptive SOD1 Silencing via Neonatal Intramuscular AAV Therapy Modifies Disease Trajectory in an ALS Mouse Model

This study shows that neonatal intramuscular AAV therapy targeting SOD1 in ALS mice delays disease onset, extends lifespan, and reduces neuroinflammation.

Pre-clinical evaluation of a gene therapy candidate for SOD1-ALS shows improved survival and signs of inflammation in the CNS of treated mice.

This study evaluates a gene therapy for SOD1-ALS, showing improved survival and CNS inflammation in treated mice with dose-dependent hSOD1 reduction.

Interactome screening implicates BAG6 as a suppressor of UBQLN2 misfolding in ALS-dementia

The paper identifies BAG6 as a suppressor of UBQLN2 misfolding in ALS-dementia by analyzing interactome changes in mutant UBQLN2 proteins.

Exposure to the organochlorine pesticide cis-chlordane induces ALS-like mitochondrial perturbations in stem cell-derived motor neurons

This study shows that cis-chlordane exposure causes mitochondrial dysfunction in motor neurons, resembling ALS features, and suggests its role in ALS pathogenesis.

Repulsive vs. Attractive Crowding Distinctly Regulate TDP-43 Condensates through Region-Specific Structural Dynamic

This study investigates how repulsive and attractive crowding environments affect TDP-43 condensates through distinct physical mechanisms and structural dynamics.