Amyotrophic Lateral Sclerosis Research

Su(var)3-9 mediates age-dependent increase in H3K9 methylation on TDP-43 promoter triggering neurodegeneration

The paper shows that Su(var)3-9 increases H3K9 methylation on the TDP-43 promoter with age, leading to reduced TDP-43 expression and neurodegeneration in Drosophila, mice, and humans.

TDP-43 pathology in Drosophila induces glial-cell type specific toxicity that can be ameliorated by knock-down of SF2/SRSF1.

This study shows that TDP-43 pathology in Drosophila glial cells causes systemic toxicity, which can be reduced by knocking down SF2/SRSF1.

DJ-1 products glycolic acid and D-lactate restore deficient axonal trafficking and DNA damage response in FUS and SOD1-associated amyotrophic lateral sclerosis

The paper shows that glycolic acid and D-lactate restore axonal trafficking and DNA damage response in FUS and SOD1-ALS patient-derived motoneurons.

Divergent impacts of C9orf72 repeat expansion on neurons and glia in ALS and FTD

The paper examines transcriptome and epigenome changes in C9orf72 repeat expansion-associated ALS and FTD, showing distinct gene expression patterns in different cell types and brain regions.

Disease related changes in ATAC-Seq of more than 450 iPSC-derived motor neuron lines from ALS patients and controls

The paper analyzes ATAC-seq data from iPSC-derived motor neurons of ALS patients and controls to identify disease-specific chromatin accessibility changes and their predictive power for disease progression.

Translation of dipeptide repeat proteins in C9ORF72-ALS/FTD through unique and redundant AUG initiation codons

The paper identifies AUG initiation codons for antisense DPRs in C9ORF72-ALS/FTD, showing redundancy in start codon usage and distinct translation factors for sense and antisense transcripts.

HDAC6 inhibition as a mechanism to prevent axon degeneration in the mSOD1G93A mouse model of ALS.

This study shows HDAC6 inhibition with ACY-738 stabilizes microtubules and reduces lower motor neuron degeneration in mSOD1G93A mice, but does not prevent motor function decline.

Dysregulated actin dynamics and cofilin correlate with TDP-43 pathology in sporadic amyotrophic lateral sclerosis

This study shows that dysregulated actin dynamics and cofilin phosphorylation are linked to TDP-43 pathology in sporadic ALS, suggesting potential therapeutic targets.

KCC2 as a novel biomarker and therapeutic target for motoneuron degenerative disease

This study identifies KCC2 as an early biomarker and therapeutic target for ALS by showing its downregulation in motor neurons and the ability of KCC2-enhancing compounds to delay disease progression.

Spinal cord and brain concentrations of riluzole after oral and intrathecal administration: a potential new treatment route for amyotrophic lateral sclerosis

This study evaluates intrathecal riluzole delivery in dogs to achieve spinal cord concentrations comparable to oral dosing without systemic side effects or elevated brain concentrations.

HuD (ELAVL4) gain-of-function impairs neuromuscular junctions and induces apoptosis in in vitro and in vivo models of amyotrophic lateral sclerosis

This study shows that HuD overexpression impairs neuromuscular junctions and induces apoptosis in ALS models, while its knockdown rescues these defects.

Synaptic Expression of TAR-DNA-Binding Protein 43 in the Mouse Spinal Cord Determined Using Super-Resolution Microscopy

This study uses super-resolution microscopy to characterize phosphorylated TDP-43 expression in spinal cord synapses of ALS mice and healthy controls.

IFNγ protects motor neurons from oxidative stress via enhanced global protein synthesis in FUS-associated Amyotrophic Lateral Sclerosis

This study shows that IFNγ treatment reduces apoptosis and improves translation rates in ALS6 patient-derived motor neurons under oxidative stress.

Multiomic ALS signatures highlight sex differences and molecular subclusters and identify the MAPK pathway as therapeutic target

The paper performs a multiomic analysis of ALS patients and mouse models to identify sex differences, molecular subclusters, and the MAPK pathway as a therapeutic target.

A panel of TDP-43-regulated splicing events verify loss of TDP-43 function in amyotrophic lateral sclerosis brain tissue

The paper identifies TDP-43-regulated splicing events in ALS brain tissue and validates them as markers of TDP-43 loss of function using in vitro models and bulk RNA-sequencing.

C9orf72 poly(PR) mediated neurodegeneration is associated with nucleolar stress

This study shows that C9orf72 poly(PR) causes nucleolar stress and neurotoxicity, which can be mitigated by reducing p53 levels in fly and rat models.

Human Herpesvirus 8 ORF57 protein is able to reduce TDP-43 pathology: Network analysis Identifies Interacting Pathways

The paper shows that ORF57 from Human Herpesvirus 8 reduces TDP-43 aggregation and cell death by interacting with ISR components.

RNA and FUS act in concert to prevent TDP-43 spatial segregation

The paper shows that FUS and TDP-43 interact in mRNA-rich compartments, with FUS enabling TDP-43 to mix and prevent aggregation, and that this interaction is disrupted by pathological mutations.

Genetic and phenotype analyses of primary lateral sclerosis datasets from international cohorts

This study analyzes genetic and clinical data from PLS patients to assess the role of genetic testing and identify potential disease-associated variants.

EphrinB2 knockdown in cervical spinal cord preserves diaphragm innervation in a mutant SOD1 mouse model of ALS

This study shows that reducing ephrinB2 in spinal cord astrocytes of ALS mice preserves diaphragm innervation and respiratory function.

PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons

The paper generates C9orf72 DPR knock-in mice and identifies an extracellular matrix signature in C9ALS/FTD that is conserved across species and protected by TGF-β1 and COL6A1.

Dysregulated TDP-43 proteostasis perturbs excitability of spinal motor neurons during brainstem-mediated fictive locomotion in zebrafish

This study shows that TDP-43 overexpression reduces excitability of spinal motor neurons during fictive locomotion in zebrafish.

Rescue of FTLD-associated TDP-43 pathology and neurodegeneration by peripheral AAV-mediated expression of brain-penetrant progranulin

Peripheral AAV-mediated delivery of brain-penetrant PGRN rescues TDP-43 pathology, neurodegeneration and motor phenotypes in FTLD-GRN models.

ENGRAILED-1 transcription factor exerts a paracrine neurotrophic activity on adult spinal cord α-motoneurons.

This study shows ENGRAILED-1 has paracrine neurotrophic effects on spinal cord α-motoneurons, with loss of function leading to motoneuron loss and limb weakness.

Characterizing proteomic and transcriptomic features of missense variants in amyotrophic lateral sclerosis genes

The paper characterizes proteomic and transcriptomic features of missense variants in ALS genes and identifies enriched structural and functional properties associated with pathogenicity.

Reduction of Nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43-related neurodegeneration

This study shows that reducing Nemo-like kinase enhances lysosome biogenesis and improves TDP-43 clearance, alleviating neurodegeneration in mouse models.

Multimodal layer modelling reveals in-vivo pathology in ALS

This study uses 7T-MRI and multimodal layer modeling to identify layer-specific pathology in early-stage ALS patients, revealing distinct iron and calcium accumulation patterns and their relationship to demyelination.

G2C4 targeting antisense oligonucleotides potently mitigate TDP-43 dysfunction in C9orf72 ALS/FTD human neurons

This study shows that targeting G2C4 antisense repeat RNA, not G4C2 sense RNA, mitigates TDP-43 dysfunction in C9orf72 ALS/FTD patient neurons, explaining the failure of previous G4C2 ASO clinical trials.

A transient protein folding response targets aggregation in the early phase of TDP-43-mediated disease

This study identifies a transient protein folding response in early TDP-43 disease that reduces aggregation, with DNAJB5 as a protective factor, and shows proteomic similarities between mouse and human TDP-43 proteinopathies.

Inhibiting toxicity of ALS-linked dipeptide repeat proteins by polystyrene sulfonate (PSS)

This study shows that polystyrene sulfonate (PSS) reduces toxicity of ALS-linked dipeptide repeat proteins in cellular and iPSC-derived motor neuron models.