Amyotrophic Lateral Sclerosis Research

C9orf72-associated G4C2 hexanucleotide repeat expression in Drosophila mushroom bodies causes age dependent TDP-43 pathology and dementia relevant phenotypes mediated in part by the glypican Dlp/GPC6

This study shows that expressing G4C2 repeats in Drosophila mushroom bodies causes age-dependent TDP-43 pathology and dementia-like phenotypes, with Dlp/GPC6 playing a role in synaptic loss.

NEK1 autophosphorylation is disrupted by amyotrophic lateral sclerosis-associated missense variants: activity biomarkers and structural insights

Kinase-dead controls, XIC quantification and phosphospecific antibodies establish pSer14, pThr156 and pSer418 as NEK1 autophosphorylation sites; a pThr156 assay shows ALS missense variants differ, with R261C reducing it most.

Scp160 deletion suppresses TDP-43 aggregation and toxicity in Saccharomyces cerevisiae

This study shows that deleting Scp160 reduces TDP-43 aggregation and toxicity in yeast, while Bfr1 has a lesser effect.

Small molecules targeting ARF1 interaction with C9orf72:SMCR8:WDR41 complexes suppress its overactivation implicated in ALS/FTD

This study identifies a small molecule, SCC944, that targets ARF1-CSW interactions and reduces GTP-bound ARF1, showing potential as a therapeutic for ALS/FTD.

Integrative synaptosome multi-omics reveals disrupted synapse organization and localized cryptic transcripts in C9ORF72-Frontotemporal Dementia

This study uses multi-omic profiling of synaptosomes to identify molecular changes in C9-FTD, revealing disrupted synaptic pathways and localized cryptic transcripts.

Selective targeting of the oligodendroglial GPR17 receptor improves myelin integrity and motor function in female SOD1G93A mice

This study shows that targeting GPR17 in oligodendrocytes improves myelin and motor function in female ALS mice but not males.

Acute Viral Infection Accelerates Neurodegeneration in a Mouse Model of ALS

Acute viral infection accelerates ALS progression in SOD1G93A mice by inducing gliosis and metabolic dysregulation, which can be mitigated by anti-inflammatory or antiviral treatments.

Cellular modifiers of TDP-43 phase transition and cytoplasmic aggregation

This study identifies cellular factors that modulate TDP-43 phase behavior and shows that nuclear export inhibition reduces its aggregation in a brain organoid model.

Autophagy induction mitigates FUS aggregate formation and early synaptic dysfunction at the NMJ in the FUS-ALS model

This study shows that inducing autophagy reduces FUS aggregate formation and synaptic dysfunction in an ALS model.

TDP-43 controls RNA structure through high affinity lattice interactions

This study shows TDP-43 binds to GU repeats with high affinity, prevents pUG fold formation, and reveals an interplay between RNA folding and protein recognition.

Distinct Cellular Phenotypes of Language and Executive Decline in Amyotrophic Lateral Sclerosis

The paper maps cognitive impairments in ALS by integrating spatial and single-nucleus transcriptomics, revealing distinct cellular and molecular patterns in language and executive dysfunction.

ROMO1 loss in cholinergic neurons induces mitochondrial ultrastructural damage and ALS-like neuromuscular degeneration

This study shows that loss of ROMO1 in cholinergic neurons causes mitochondrial damage and ALS-like symptoms in mice.

AAV-Delivered Anti-PC-OxPL Antibody Fragments: A NovelTherapeutic Approach to Target ALS

This paper develops an AAV-delivered scFv antibody targeting PC-OxPL to reduce neurotoxicity and motor neuron death in ALS models.

A Phosphorylation-Induced Micellization switch in the low complexity domain of TDP-43

This study shows phosphorylation of TDP-43's low-complexity domain shifts its self-assembly from macrophase separation to micellization, potentially protecting against pathological aggregation.

Neuro-glial lipid imbalance in a Drosophila model of Amyotrophic Lateral Sclerosis 8

This study identifies lipid imbalance in a Drosophila ALS8 model, showing that VAPB activity regulates lipid homeostasis in neurons and glia.

Transplantation of Human IPSC-derived Microglia Ameliorates Neuropathology and Circuit Dysfunction in Progranulin-Deficient Mice

This study shows that transplanting wild-type human iPSC-derived microglia into progranulin-deficient mice reduces neuropathology, circuit dysfunction, and behavioral issues in a FTD model.

TAF15 amyloids propagate via defined motifs in a prion-like fashion

This study shows TAF15 forms amyloid fibrils and propagates prion-like between cells, identifying specific motifs that drive its aggregation in vitro and in cells.

Recurrent patterns of TOP1-mediated neuronal genomic damage shared by major neurodegenerative disorders

The paper identifies a shared TOP1-mediated mutagenic mechanism in ALS, FTD, and AD through single-cell genomic analysis and experimental validation.

Lack of motor defects and ALS-like neuropathology in heterozygous Sptlc1 Exon 2 deletion mice

This study creates a mouse model with a heterozygous deletion of Sptlc1 exon 2 and finds no motor defects or ALS-like neuropathology, but homozygous mutants die prematurely.

Intrathecal (G4C2)149 delivery in C9orf72-deficient mice yields mild motor dysfunction and ALS/FTD pathological hallmarks

This paper delivers (G4C2)149 repeats intrathecally in C9orf72-deficient mice, revealing mild motor dysfunction and ALS/FTD pathological features.

Chronic diazepam reveals excessive homeostatic gain in SOD1G93A mouse spinal motoneurons

This study shows that SOD1G93A mouse motoneurons exhibit exaggerated homeostatic responses to chronic diazepam inhibition compared to wild-type motoneurons.

Cryptic splicing in synaptic and membrane excitability genes links TDP-43 loss to neuronal dysfunction

This study identifies TDP-43-dependent cryptic splicing events in synaptic and membrane excitability genes and shows they drive neuronal dysfunction in ALS and FTD.

miR-146a is a Pleiotropic Regulator of Motor Neuron Degeneration

The paper shows miR-146a regulates multiple aspects of motor neuron degeneration in ALS, with genetic deletion extending survival and causing age-related paralysis and inflammation.

Multimodal analysis of cell-free DNA identifies epigenetic biomarkers for amyotrophic lateral sclerosis diagnosis and progression

This study identifies epigenetic biomarkers in cell-free DNA for ALS diagnosis and progression prediction using methylation analysis.

Effects of lysine deacetylation inhibition alone or in combination with arimoclomol on TDP-43 proteinopathy

This study investigates the effects of HDAC inhibition and its combination with arimoclomol on TDP-43 proteinopathy in vitro and in vivo, finding delayed pathology and synergistic neuroprotection.

Reevaluating the Role of Beta2-Microglobulin: New Insights on Selective Vulnerability in ALS Pathology

This study investigates the role of beta2-microglobulin and HLA in motor neuron vulnerability in ALS, finding dynamic regulation but not major disease modification.

ALS mutations do not alter perineuronal net formation in human stem cell-derived motor neurons

The paper investigates whether ALS mutations affect PNN formation in human stem cell-derived motor neurons and finds no alteration in PNN-like structures or gene expression.

TDP-43 expression in the cytoplasm leads to early synaptic and mitochondrial abnormalities in an inducible mouse model of ALS/FTD

This study shows that cytoplasmic TDP-43 expression in mice leads to early synaptic and mitochondrial abnormalities linked to behavioral deficits in ALS/FTD.

Short RNA chaperones promote aggregation-resistant TDP-43 conformers to mitigate neurodegeneration

Short UG-rich RNAs bind and stabilize TDP-43 RNA-recognition motifs to allosterically destabilize its prion-like domain helical region, preventing aggregation and mitigating neurodegeneration in cells and mice.

Dysregulated lactate metabolism synergizes with ALS genetic risk factors to accelerate motor decline

The paper investigates how partial disruption of lactate metabolism, specifically through LDHB loss, synergizes with ALS genetic risk factors to accelerate motor decline.