Amyotrophic Lateral Sclerosis Research

Towards a diagnostic test for sporadic ALS utilising deep learning and SNP microarrays

This paper develops a deep learning model using SNP microarray data to predict ALS risk with high accuracy across diverse populations and genotyping platforms.

A role for astrocytic miR-129-5p in Frontotemporal Dementia

This study identifies miR-129-5p as a deregulated microRNA in FTD patients, showing its role in astrocyte dysfunction and neurodegeneration.

Skin TDP-43 pathology as a candidate biomarker for predicting amyotrophic lateral sclerosis decades prior to motor symptom onset

This study identifies pre-symptomatic TDP-43 pathology in skin and other peripheral organs up to 26.5 years before ALS diagnosis, suggesting skin as a potential biomarker for early detection.

Allele-specific silencing of a dominant SETX mutation in familial amyotrophic lateral sclerosis type 4

The paper demonstrates that allele-specific siRNA can effectively silence a dominant SETX mutation in ALS4, restoring R-loop levels in patient cells.

ASO-mediated knockdown of GPNMB in mutant-GRN and Grn-deficient peripheral myeloid cells disrupts lysosomal function and immune responses

This study shows that reducing GPNMB in progranulin-deficient myeloid cells impairs lysosomal function and immune responses, suggesting GPNMB is essential for maintaining immune homeostasis.

Context-dependent Interactors Regulate TDP-43 Dysfunction in ALS/FTLD

The paper identifies context-dependent interactors of TDP-43 that regulate its dysfunction in ALS/FTLD using proximity labeling, mass spectrometry, and snRNA-seq integration.

5-ethynyluridine perturbs nuclear RNA metabolism to promote the nuclear accumulation of TDP-43 and other RNA binding proteins

This study shows that 5-ethynyluridine (5EU) causes nuclear accumulation of TDP-43 and other RNA-binding proteins by altering RNA metabolism and splicing.

Differential neuronal vulnerability to C9orf72 repeat expansion driven by Xbp1 transcription signature

The paper identifies neuronal vulnerability to C9orf72 repeat expansion by analyzing transcriptional states in a Drosophila model, finding that Xbp1 expression correlates with resistance to toxicity.

Computational analysis of SOD1-G93A mouse muscle biomarkers for comprehensive assessment of ALS progression

The paper identifies image biomarkers in SOD1-G93A mouse muscle biopsies that track ALS progression from presymptomatic to advanced stages using computational analysis.

Somatic mutations in ALS genes in the motor cortex of sporadic ALS patients

This study identifies somatic mutations in ALS genes in the motor cortex of sporadic ALS patients, particularly in excitatory neurons, suggesting a role in disease initiation.

Cytoplasmic accumulation of a splice variant of hnRNP A2/B1 contributes to FUS-associated toxicity in a mouse model of ALS

This study shows that FUS-induced splicing changes lead to cytoplasmic accumulation of hnRNP A2b/B1 splice variants, promoting stress granule formation and motor neuron toxicity in a mouse model of ALS.

A stress-dependent TDP-43 SUMOylation program preserves neuronal function

This study shows that TDP-43 SUMOylation is a stress response that protects neurons, and its disruption is linked to aging and disease.

Charged mutations in the FUS low-complexity domain modulate condensate ageing kinetics

This study uses simulations to show how charged mutations in FUS affect condensate ageing kinetics by altering β-sheet accumulation and aggregate formation.

Disassembly of ALS condensates by a disordered peptide

This study identifies an RGG peptide that disassembles ALS-associated condensates by reducing toxicity and restoring nuclear localization in FUS mutants.

Downregulation of Keratin Proteins in the Neuroendocrine System of Amyotrophic Lateral Sclerosis with PT150 as a Dual Neuroprotectant

The paper uses a Graph Neural Network to diagnose ALS with high accuracy and identifies keratin proteins and PT150 as potential biomarkers and therapeutics.

Neuromuscular dysfunction in patient-derived FUSR244RR-ALS iPSC model via axonal downregulation of neuromuscular junction proteins

The paper establishes an ALS hiPSC model showing axonal downregulation of neuromuscular junction proteins and identifies FUS binding to their mRNAs.

Artificial intelligence-augmented drug discovery identifies gefitinib as a potential treatment for ALS

This paper uses AI to identify gefitinib as a potential ALS treatment, showing it protects motor neurons and reduces TDP-43 fragments in vitro and in vivo.

Synaptic changes contribute to persistent extra-motor behaviour deficits in the rNLS8 TDP-43 mouse model of amyotrophic lateral sclerosis

This study identifies persistent extra-motor behavioural deficits in rNLS8 TDP-43 mice, linked to synaptic gene expression and splicing changes that persist even after motor recovery.

Fingerprinting disease-derived protein aggregates reveals unique signature of Motor Neuron Disease

This study uses single molecule microscopy to fingerprint TDP-43 aggregates in brain tissue, distinguishing MND donors from controls and different MND cohorts.

ALS molecular subtypes are a combination of cellular, genetic, and pathological features learned by deep multiomics classifiers

This study introduces DANcer, a deep learning classifier that identifies robust ALS molecular subtypes across bulk and single-cell datasets, showing they correlate with clinical features and cellular mechanisms.

Citrullination of TDP-43 is a key post-translation modification associated with structural and functional changes and progressive pathology in TDP-43 mouse models and human proteinopathies

This study identifies citrullination as a novel irreversible post-translational modification of TDP-43 linked to structural changes, aggregation, and pathology in TDP-43 proteinopathies.

C9orf72-ALS mutation drives mitophagy impairments in iNeurons

This study shows that C9orf72-ALS mutation impairs mitophagy in iNeurons by reducing autophagosome production and ULK1 recruitment to mitochondria.

pTDP-43 levels correlate with cell type specific molecular alterations in the prefrontal cortex of C9orf72 ALS/FTD patients

The paper identifies cell type-specific molecular changes in the prefrontal cortex of C9orf72 ALS/FTD patients correlated with pTDP-43 levels.

Neuronal polyunsaturated fatty acids are protective in FTD/ALS

The paper identifies reduced PUFA levels in FTD/ALS models and shows neuronal PUFA supplementation improves survival and reduces neuronal death.

TDP-43 directly inhibits RNA accumulation in neurites through modulation of RNA stability

This study shows TDP-43 inhibits RNA accumulation in neurites by modulating RNA stability, with ALS mutations causing similar mislocalization.

TDP-43 pathology is sufficient to drive axon initial segment plasticity and hyperexcitability of spinal motoneurones in vivo in the TDP43-ΔNLS model of Amyotrophic Lateral Sclerosis

This study shows that TDP-43 pathology in the TDP43-ΔNLS mouse model drives hyperexcitability in spinal motoneurones, with reversible effects upon transgene resuppression.

Astrocytic activation of EMMPRIN contributes to their pathological phenotype in ALS.

The paper shows that EMMPRIN activation in astrocytes contributes to their pathological phenotype in ALS and suggests anti-EMMPRIN antibodies as a potential therapeutic approach.

Compositional control of ageing kineticsin TDP-43 condensates

This study uses Molecular Dynamics simulations to show how different biomolecules affect the ageing kinetics of TDP-43 condensates, with arginine-rich peptides accelerating and poly-Uridine RNA slowing the formation of harmful cross-β-sheet structures.

Neuronal TDP-43 aggregation drives changes in microglial morphology prior to immunophenotype in amyotrophic lateral sclerosis

This study shows that microglial morphology changes before immunophenotype shifts in ALS, driven by TDP-43 aggregation, suggesting morphological changes may trigger immunological responses.

The oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling, and therapeutic implications

The paper investigates oligogenic risk in ALS using genome sequencing data, finding that multiple rare variants in known ALS genes increase disease risk but not clinical outcomes.