Amyotrophic Lateral Sclerosis Research

Zfp106 binds to G-quadruplex RNAs and inhibits RAN translation and formation of RNA foci caused by G4C2 repeats

This study shows Zfp106 binds to G-quadruplex RNAs formed by GGGGCC repeats, inhibiting RAN translation and RNA foci formation in C9orf72-related diseases.

ASO-enhancement of TARDBP exitron splicing mitigates TDP-43 proteinopathies

This paper shows that enhancing TARDBP exitron splicing reduces TDP-43 aggregation and neurodegeneration in disease models using ASOs.

Loss of MEF2C function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice

This study shows that an enhancer mutation in MEF2C causes mitochondrial dysfunction and motor deficits in mice by impairing mitochondria-encoded gene expression.

CUTS RNA Biosensor for the Real-Time Detection of TDP-43 Loss-of-Function

The paper introduces CUTS, a biosensor for real-time detection of TDP-43 loss-of-function, showing its sensitivity, accuracy, and potential for gene therapy applications.

TDP-43 mutations-induced defects in miRNA biogenesis and cytotoxicity by differentially obstructing Dicer activity in Drosophila and in vitro

This study shows TDP-43 mutations disrupt miRNA biogenesis by affecting Dicer activity, leading to cytotoxicity in Drosophila and in vitro models.

Conserved loop of a phase modifier endows protein condensates with fluidity

This study identifies Kapβ2 as a target of DPRs, showing how DPR binding alters its phase-modifying function, leading to toxic RBP condensates in ALS models.

TDP43 autoregulation gives rise to shortened isoforms that are tightly controlled by both transcriptional and post-translational mechanisms

This study identifies TDP43 autoregulation as a source of shortened isoforms, showing they are regulated by NMD and post-translational degradation, and their dysregulation leads to neurodegeneration.

Single-nucleus sequencing reveals enriched expression of genetic risk factors in Extratelencephalic Neurons sensitive to degeneration in ALS

The paper identifies cell type-specific molecular changes in ALS patients, showing enrichment of genetic risk factors in extratelencephalic neurons and altered responses in oligodendrocytes and microglia.

Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction in C9orf72 ALS/FTD in vivo models and patient iNeurons

This study shows that activating the Keap1/Nrf2 pathway reduces mitochondrial dysfunction and motor deficits in C9orf72 ALS/FTD models and patient-derived neurons.

Loss of TDP-43 induces synaptic dysfunction that is rescued by UNC13A splice-switching ASOs

This study shows that loss of TDP-43 causes synaptic dysfunction through a cryptic exon in UNC13A, which is rescued by antisense oligonucleotides.

Hetero-oligomerization of TDP-43 carboxy-terminal fragments with cellular proteins contributes to proteotoxicity

This study shows that truncated RRM in TDP-43 CTFs causes structural changes in IDR, leading to toxic hetero-oligomers and cell-nonautonomous toxicity in nematodes.

M6A reduction relieves FUS-associated ALS granules

The paper shows that reducing m6A content via METTL3 knock-down decreases FUS-associated ALS granules in cell models and patient-derived fibroblasts.

TMEM106B C-terminal fragments aggregate and drive neurodegenerative proteinopathy.

This study identifies TMEM106B C-terminal fragments as aggregating proteins linked to neurodegenerative diseases and shows their toxic effects in a C. elegans model.

Frontotemporal dementia-like disease progression elicited by seeded aggregation and spread of FUS

This study shows that injecting human FUS fibrils into mice with human FUS causes FUS aggregation and FTLD-like disease progression, with prion-like spread and cognitive deficits.

Elevated nuclear TDP-43 induces constitutive exon skipping

This study shows that elevated nuclear TDP-43 causes species-specific exon skipping, which differs from exon skipping seen in TDP-43 loss-of-function, highlighting the need for careful interpretation of TDP-43 overexpression models.

Stabilization of V1 interneuron-motor neuron connectivity ameliorates motor phenotype in a mouse model of ALS

This study shows that stabilizing V1 interneuron-motor neuron connectivity in ALS mice improves motor function by enhancing motor neuron survival.

FDA approved PDE4 inhibitors reduce the dominant toxicity of ALS/FTD associated CHCHD10S59L

The paper shows FDA-approved PDE4 inhibitors reduce mitochondrial defects and toxicity caused by CHCHD10S59L mutations in human cells and Drosophila models.

Amyloidogenic regions in beta-strands II and III modulate the aggregation and toxicity of SOD1 in living cells

The paper identifies amyloidogenic regions in beta-strands II and III of SOD1 that modulate aggregation and toxicity in ALS mutants, showing that proline mutations reduce these effects.

Spinal inhibitory neurons degenerate before motor neurons and excitatory neurons in a mouse model of ALS

The paper investigates spinal interneuron degeneration in an ALS mouse model, finding inhibitory neurons degenerate earlier and more slowly than excitatory neurons and motor neurons.

Targeting complement C3a receptor resolves mitochondrial hyperfusion and subretinal microglial activation in progranulin-deficient frontotemporal dementia

This study identifies a mechanism by which progranulin deficiency leads to mitochondrial hyperfusion and neuroinflammation in GRN-FTD, showing that targeting C3aR can restore mitochondrial integrity and reduce microglial activation.

Fibroblasts carrying intermediate C9orf72 hexanucleotide repeat expansions from iNPH patients show impaired energy metabolism but no cell pathologies

Sex-specific risk loci and modified MEF2C expression in ALS

The paper identifies sex-specific risk loci for ALS, including MEF2C, which is upregulated in female ALS motor neurons, and an X-chromosome locus at IL1RAPL2.

Proteomic analysis of the TDP-43-associated insoluble fraction from NEFH-TDP-43 mouse brain suggests sustained stress granule formation, CLUH granule recruitment and impaired mitochondrial metabolism

The paper isolates and analyzes the proteome of TDP-43-associated insoluble stress granules in an ALS mouse model, identifying sustained stress granule formation, CLUH granule recruitment, and impaired mitochondrial metabolism.

Mitochondrial dysfunction heightens the integrated stress response to drive ALS pathogenesis

This study shows that VAPB P56S mutation causes mitochondrial dysfunction and enhances the integrated stress response, leading to motor neuron disease in ALS.

Maximising the translational potential of neurophysiology in amyotrophic lateral sclerosis: a study on compound muscle action potentials

This study compares compound muscle action potentials (CMAPs) in SOD1G93A mice and human ALS patients to identify translational alignment points for disease progression.

NEK1 modulates neurite outgrowth in motor neurons through coordinating retromer formation

This study identifies NEK1's role in motor neuron neurite outgrowth by coordinating retromer formation through interactions with SMC3.

Biochemical, biomarker, and behavioral characterization of the GrnR493X mouse model of frontotemporal dementia

This study characterizes the GrnR493X mouse model of frontotemporal dementia, finding similar phenotypes to Grn knockout models but with differences in biomarker levels in heterozygous mice.

Mutation of the ALS/FTD-associated RNA-binding protein FUS alters axonal cytoskeletal organisation

The paper investigates how mutations in the FUS protein affect axonal cytoskeletal organisation in ALS/FTD models, finding reduced actin density and axonal branch complexity.

Glucose Hypometabolism Prompts RAN Translation and Exacerbates C9orf72-related ALS/FTD Phenotypes

This study shows glucose hypometabolism in C9orf72-related ALS/FTD leads to DPR production, neuronal death, and motor dysfunction through GCN2 activation.

Antisense RNA C9orf72 Hexanucleotide Repeat Associated With Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Forms A Triplex-Like Structure and Binds Small Synthetic Ligand

This study determines the crystal structure of antisense C9orf72 hexanucleotide repeat RNA with and without a ligand, revealing its triplex-like structure and ligand binding mechanism.