Amyotrophic Lateral Sclerosis Research

Characterization of a C9orf72 Knockout Danio rerio model for ALS and cross-species validation of potential therapeutics screened in Caenorhabditis elegans.

The paper develops a zebrafish C9orf72 knockout model for ALS, identifies pizotifen malate as a potential therapeutic, and validates its efficacy in both zebrafish and C. elegans models.

LINC00205 acts as a multivalent scaffold promoting FUSP525L recruitment in Amyotrophic Lateral Sclerosis stress granules

This study identifies LINC00205 as a critical lncRNA that promotes the formation of pathological stress granules in ALS by acting as a scaffold to recruit specific mRNAs and proteins.

Corticospinal propagation of full-length TDP-43 toxicity drives brain-to-muscle pathology

This study shows that full-length TDP-43 spreads from the brain to muscle in rats, causing pathology and dysfunction.

Herpes simplex virus infection promotes ALS pathology through ICP0-mediated PML body disruption

This study shows HSV infection increases ALS risk and promotes TDP-43 pathology through ICP0-mediated disruption of PML bodies.

A mitochondrial tipping point couples early hyperexcitability to late-stage failure in patient-derived ALS motor neurons

This study shows that early hyperexcitability in ALS patient-derived motor neurons drives mitochondrial hypermetabolism, which later leads to mitochondrial failure and neuron loss.

Granulin loss and TMEM106B risk converge on lysosomal C-terminal fragment pathology in frontotemporal dementia

The paper shows granulin deficiency leads to lysosomal buildup of a TMEM106B C-terminal fragment, explaining how TMEM106B alleles influence FTD risk.

Seeded aggregation of ANXA11 induces prion-like propagation, TDP-43 co-pathology and nucleocytoplasmic transport defects

This study shows ANXA11 forms prion-like amyloid fibrils through phase separation, which propagate between cells, induce TDP-43 pathology, and disrupt nucleocytoplasmic transport, linking ANXA11 dysfunction to ALS/FTD.

Modulation of biomolecular aggregate morphology and condensate infectivity

This study investigates how interactions between RNA and the prion-like domain of hnRNPA1 influence aggregate morphology and infectivity in neurodegenerative diseases.

Riluzole treatment paradoxically increases motoneuron excitability in ALS due to hyperactive homeostasis

This study shows that riluzole increases motoneuron excitability in ALS mice due to hyperactive homeostasis, which counteracts the drug's intended effects.

ALS mutations disrupt self-association between the Ubiquilin Sti1 hydrophobic groove and internal placeholder sequences

This study presents the first crystal structure of the Ubiquilin Sti1 domain bound to a transmembrane domain, showing that ALS mutations disrupt their interaction and reveal internal placeholder sequences that regulate phase separation.

Metabolic signatures of ferritin and TDP-43 co-pathology provide a mechanistic basis for stratified therapeutic approaches in ALS

This paper identifies distinct metabolic signatures in ALS subtypes defined by ferritin and TDP-43 pathology, supporting stratified therapeutic approaches.

A chemical inducer of ribophagy limits the toxicity of ALS-related arginine-rich peptides

The paper identifies a chemical inducer of ribophagy, SALSa, that reduces toxicity of ALS-related arginine-rich peptides and extends lifespan in a Drosophila model.

Aldh3a1-mediated detoxification of reactive aldehydes contributes to distinct muscle responses to Amyotrophic Lateral Sclerosis progression

This study identifies Aldh3a1's role in protecting muscles from ALS progression by detoxifying reactive aldehydes, showing differential expression and functional importance across muscle types.

Pml loss worsens NEK1-linked ALS and Pml induction drives NEK1 degradation, precluding disease onset

This study shows that Pml loss worsens NEK1-linked ALS, while Pml induction reduces disease symptoms by clearing Nek1t aggregates.

Spinal motoneuron excitability is homeostatically-regulated through β-adrenergic neuromodulation in wild-type and presymptomatic SOD1 mice

This study shows that β-adrenergic receptors regulate spinal motoneuron excitability through homeostatic feedback in both wild-type and presymptomatic SOD1 mice.

Ropinirole hydrochloride mitigates oxidative stress and neuroinflammation via the PI3K-mTOR pathway in TDP-43 hiPSC-derived microglial-like cells

This study shows ropinirole hydrochloride reduces oxidative stress and neuroinflammation in TDP-43 mutant microglial-like cells by modulating the PI3K-mTOR pathway.

Fructose-2,6-bisphosphate restores TDP-43 pathology-driven genome repair deficiency in motor neuron diseases

This study shows that fructose-2,6-bisphosphate (F2,6BP) restores genome repair and motor function in TDP-43 pathology-driven motor neuron diseases.

Intracellular TDP-43 amyloid nucleates from arrested nascent condensates

This study shows TDP-43 amyloid forms only when its C-terminal domain arrests in soluble clusters, and this process can be inhibited by co-expressing an oligomeric binder.

Regulation of transcription termination by FUS and TDP-43

This study shows that TDP-43 and FUS are recruited by the R1810me2s-SMN pathway, and their defects affect RNAPII termination and R-loop accumulation, contributing to neurodegenerative disorders.

Fos regulates age-dependent neuroinflammation in VAPBALS

The paper identifies Fos as a regulator of age-dependent neuroinflammation in a Drosophila model of ALS8, showing its role in modulating inflammation and motor function.

cGAS inhibition delays TDP-43-driven ALS Pathogenesis

This study identifies cGAS as a key mediator of TDP-43 pathology in ALS and shows that its inhibition reduces RNA splicing defects and neurodegeneration.

Novel single molecule imaging approaches reveal structure-function alterations to the nuclear pore complex in early C9ORF72-associated TDP-43 proteinopathy

The paper develops new single molecule imaging techniques to study how C9ORF72-linked poly(glycine-arginine) peptides disrupt nuclear pore transport and structure, linking these changes to early TDP-43 pathology in ALS/FTD.

Breaking β-sheets in FUS prion-like domain preserves phase separation and function but prevents aggregation and toxicity

This study introduces β-sheet breaking proline residues into FUS prion-like domain to prevent aggregation and toxicity while preserving phase separation and function.

Neuronal Cell-Cycle Re-entry Defines Divergent Outcomes Through Replication-Dependent DNA Damage in ALS

The paper shows that cell-cycle re-entry in motor neurons correlates with distinct ALS outcomes and identifies CDK4/6 inhibition as a potential neuroprotective strategy.

TRIM32-UBQLN2-p62 axis promotes TDP-43 inclusion formation and amyloid aggregation through shuttle condensates

This study identifies a molecular pathway involving TRIM32, UBQLN2, and p62 that forms condensates promoting TDP-43 aggregation in neurodegenerative diseases.

Repeat expansions in C9orf72 rewire the 3D chromatin landscape in ALS

This study shows that C9orf72 repeat expansions alter chromatin loops in neurons, linking RNA-DNA interactions to gene dysregulation in ALS.

Novel extracellular vesicle release pathway facilitated by toxic superoxide dismutase 1 oligomers

The paper investigates how toxic SOD1 oligomers affect extracellular vesicle release pathways in ALS, identifying key proteins and pathways involved.

Small heat shock protein HSPB8 interacts with a pre-fibrillar TDP43 low complexity domain species to delay fibril formation

This study shows HSPB8 interacts with TDP43's low complexity domain to delay fibril formation without affecting elongation rates.

APOE ε4 defines a systemic immune endophenotype independent of clinical trajectory in amyotrophic lateral sclerosis

This study identifies an APOE ε4-associated systemic immune proteomic signature in ALS that predicts disease progression independently of clinical features.

Divergent mitochondrial and metabolic adaptations shape selective vulnerability in ALS

The paper identifies divergent mitochondrial and metabolic profiles between ALS-vulnerable and resilient neurons, revealing how these differences contribute to selective vulnerability in ALS.