Amyotrophic Lateral Sclerosis Research

Multiscale Transcriptomic Architecture of the ALS Motor Cortex

The paper identifies seven subtypes of ALS motor cortex with distinct molecular programs and shows they are organized by genetic and clinical factors rather than disease duration.

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.

ALSmiR: a curated evidence resource for ALS-associated microRNAs for biomarker discovery

ALSmiR is a curated database of microRNA expression findings in ALS patients, providing context and results for biomarker discovery.

TDP-43 amyloid conversion in cells tracks the net charge of a polyampholyte motif, not condensate solidification

Temporal RNA splicing dysregulation in a human multicellular model of C9orf72 ALS

This study uses human spinal cord organoids to model C9orf72 ALS, identifying early RNA splicing dysregulation and RBP network dysfunction as key features of the disease.

ALS-associated mutations reveal a conserved C-terminal self-assembly module in the TDP-43 low-complexity domain

The paper identifies the C-terminal conserved region (CCR) of TDP-43 as a self-assembly module, showing that ALS-associated mutations impair fibrillization and assembly kinetics.

CCT2 expression marks a translation-activated state in sporadic ALS motor neurons and is associated with functional decline

The paper identifies CCT2 as a marker of a translation-activated state in sporadic ALS motor neurons and links it to functional decline.

Engineered Chimeric Proteins Functionally Replace ALS-causing Endogenous FUS and TDP-43 to Improve Neuronal Health

The paper engineers chimeric proteins to replace ALS-causing FUS and TDP-43, improving neuronal health by reducing aggregation and restoring nuclear functions.

Multi-Domain Interplay Controls Full-Length TDP-43 Phase Separation and Condensate Dynamics

This study shows how different domains of TDP-43 interact to control phase separation and condensate dynamics through simulations and experiments.

Somatic instability of the C9orf72 repeat expansion in blood differs between patients with amyotrophic lateral sclerosis or frontotemporal dementia.

This study uses optical genome mapping to analyze C9orf72 repeat expansion instability in blood from ALS and FTD patients, finding age-dependent differences in repeat size dynamics between conditions.

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.

SARS-CoV-2 Nucleocapsid Protein forms biomolecular condensates and interacts with ALS-associated RNA binding proteins in vitro

This study investigates how SARS-CoV-2 N-protein forms biomolecular condensates and interacts with ALS-associated RNA-binding proteins in vitro and human cell models.

A Framework For Large-Scale Reconstruction Of Extended Pedigrees To Facilitate Gene Discovery In ALS

This paper develops a framework to reconstruct extended pedigrees for ALS patients with the C9orf72 repeat expansion, identifying novel familial relationships and shared genomic regions.

Monomeric TDP-43 binds GU-rich RNA via its NTD but only its oligomers block cryptic exon inclusion

This study shows that the NTD of TDP-43 binds UG-rich RNA on monomers, while oligomerization is essential for repressing cryptic exons.

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.

ALS/FTD-linked TDP-43 alterations prevent HSV-1 infection by disrupting cell-adhesion pathways

This study shows that TDP-43 mutations in ALS/FTD reduce HSV-1 infection by disrupting cell-adhesion pathways and impairing viral entry.

Early life social isolation primes flies for more rapid TDP-43 dependent neurodegeneration later in life.

This study shows that early-life social isolation in flies accelerates TDP-43-related neurodegeneration later in life by enhancing mdg4 activation and pathologic propagation.

Toxicity of MAPT 4R RNA Contributes to Motor Neuron Degeneration in ALS

The paper shows that increased 4R Tau RNA contributes to motor neuron degeneration in ALS by reducing viability and that targeting this RNA could be therapeutic.

Fibers and Glasses are Competing Material States in FUS Protein Condensation

This study shows that FUS protein fibers grow in the dilute phase around condensates, which transition to a glassy state, revealing two coexisting solid-like phases in protein condensation.

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.

Targeted single-nucleus sequencing of 39,800 neurons reveals extensive low-frequency somatic variants

The paper analyzes somatic mutations in neurons from FTLD-TDP type C patients and controls, finding extensive low-frequency variants in TARDBP and other genes.

VCP is a critical component for TDP-43 disaggregase activity in skeletal muscle

This study investigates how VCP mutations affect TDP-43 aggregate clearance in skeletal muscle, finding reduced clearance capacity in vitro and in vivo.

TDP-43 dysfunction induces cryptic circular RNAs in ALS/FTD

This study identifies TDP-43 dysfunction as a cause of cryptic circular RNA formation in ALS/FTD, showing their association with disease-relevant protein loss and potential as biomarkers.

Ile35 residue of SOD1 plays a key role in aggregate formation and eye degeneration in a Drosophila model of ALS

Restoring multiple TDP-43 cryptic targets, but not solely Unc13a, rescues motor neuron disease

The paper shows that restoring multiple TDP-43 cryptic targets, not just Unc13a, rescues motor neuron disease in a mouse model of ALS.

Intergenerational instability of the C9orf72 hexanucleotide repeat

The paper investigates intergenerational instability of C9orf72 hexanucleotide repeats, finding increased instability in alleles with >20 repeats and a paternal expansion bias in 20-40 repeat alleles.

Prevention of Unc13a cryptic splicing is sufficient to preserve memory

This study shows that preventing cryptic splicing of UNC13A and other TDP-43 targets can preserve memory and reduce neuron loss in a TDP-43 knockout mouse model.

Paired RNA profiling of circulating small extracellular vesicles links survival in ALS to reactive glial - vascular programs

The paper pairs miRNA and mRNA profiles from circulating sEVs to identify survival-associated programs in ALS, finding a five-miRNA panel and a five-gene core linked to glial and vascular responses.

ARPP21 defines a TDP-43-independent aggregation pathway in amyotrophic lateral sclerosis

This study identifies ARPP21 as a TDP-43-independent aggregation pathway in ALS, showing its role in forming non-ubiquitinated aggregates and promoting intercellular propagation.