Amyotrophic Lateral Sclerosis Research

Circular RNA aptamers as superb sub-stoichiometric chaperones of TDP-43 condensation

This paper identifies two circular RNA aptamers that act as sub-stoichiometric chaperones to suppress pathological TDP-43 condensation and rescue splicing and motor dysfunction in vivo.

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.

Comprehensive characterization of skeletal muscle remodeling in hSOD1G93A mice reveals limited functional impact of systemic FOXO1 inhibition

This study investigates the effects of systemic FOXO1 inhibition in hSOD1G93A mice, finding limited therapeutic benefit in modifying disease progression or muscle pathology.

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.

An autoinhibitory regulatory switch governs heterotypic phase separation and liquid-to-solid phase transition of TDP-43 and tau into cytotoxic amyloids

The paper investigates how TDP-43 and tau undergo heterotypic phase separation and transition into cytotoxic amyloids, revealing an autoinhibitory switch that regulates this process.

The retroelement-derived human protein PEG10 is a regulator of mRNA splicing in neurons

This paper identifies PEG10 as a regulator of mRNA splicing in neurons, showing it mimics TDP-43 loss and affects NRG3 splicing in ALS patient samples.

Nuclear DNA damage is a primary driver of mitochondrial dysfunction in C9ORF72 ALS/FTD

This study shows that nuclear DNA damage directly causes mitochondrial dysfunction in C9ORF72 ALS/FTD by triggering a DNA damage response that depletes NAD+ and impairs mitochondrial bioenergetics.

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.

The accumulation of orphan ribosomal proteins is a hallmark of ALS

This study identifies the accumulation of orphan ribosomal proteins as a molecular hallmark of ALS, linking it to various ALS-related mutations and neurotoxins.

ALS mutations in the TIA1 RNA granule protein have differing effect on low complexity domain fibril formation

The paper examines how ALS-linked mutations in TIA1's low complexity domain affect fibril formation and structural conformations in stress granules.

Phosphorylation Mimicking Mutations Cause TDP-43 to Adopt Different Fibril Conformations

This study shows that phosphomimetic mutations in TDP43LC alter fibril conformation during aggregation, despite similar soluble structures.

Peripheral metabolic dysfunction drives sleep disruption in TDP-43 proteinopathy

This study shows that peripheral metabolic dysfunction, not just neuronal loss, causes sleep disruption in TDP-43 proteinopathy by identifying SIK3 as a key regulator.

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.

Single-cell transcriptomics uncovers chromatin dysfunction in a human TDP-43 proteinopathy model of Amyotrophic Lateral Sclerosis.

The paper uses single-cell RNA sequencing to show that TDP-43 mislocalisation disrupts chromatin remodelling in spinal neurons, identifying ACTL6B as a key inhibited factor in ALS.

SUMO paralogues differentially affect phase separation and aggregation of intrinsically disordered proteins

This study shows SUMO1 and SUMO2 differentially regulate TDP-43 phase separation and aggregation, with SUMO1 inhibiting and SUMO2 promoting liquid-like states that prevent aggregation.

Targeting calpastatin pharmacologically restores synaptic proteolysis and preserves motor neurons survival and function in C9orf72 ALS

This study shows that restoring calpastatin activity improves motor neuron function and survival in C9orf72 ALS models by enhancing synaptic proteolysis and NMJ integrity.

Genetic suppression of myeloid receptor Clec7a attenuates microglia neuroinflammation and promotes microglial phagocytosis to delay disease progression in ALS models

This study shows that reducing Clec7a in microglia reduces neuroinflammation and improves phagocytosis, slowing ALS progression in mouse models.

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.

Pharmacological rescue of mitochondrial dysfunction, neurite degeneration, and premature death of ALS and AD iPSC-derived neurons

This study identifies Dipyridamole as a drug that rescues mitochondrial dysfunction and neuronal death in ALS and AD iPSC-derived neurons by enhancing mitochondrial pyruvate uptake.

Generation and validation of a human iPSC-derived TDP-43 knockout model for ALS disease modeling.

The paper generates and validates a human iPSC-derived TDP-43 knockout model for ALS, showing widespread cryptic exon inclusion and identifying potential therapeutic modulators.

TMEM106B C-terminal fragments drive nucleocytoplasmic transport failure and TDP-43 mislocalization in the aging human brain

This study shows that TMEM106B C-terminal fragments cause nucleocytoplasmic transport failure and TDP-43 mislocalization in aging brains, linking them to neurodegeneration.

Predictive Cellular Signatures from Live Human Motor Neurons Distinguish TDP-43 ALS and Enable ALS Subtype Stratification

This paper uses machine learning to identify cellular signatures in human motor neurons that distinguish TDP-43 ALS subtypes and enable patient stratification.

Phosphoregulated SMCR8-FIP200 interaction connects the ALS/FTD-linked C9orf72 complex to autophagy initiation and mitochondrial quality control

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.

Microprotein Regulates G-quadruplex Driven RNA Aggregation

This study identifies ZNF706 as a microprotein that modulates G-quadruplex formation and RNA phase behavior, reducing pathological aggregates in neurodegenerative diseases.

TDP-43 pathology is linked to motor neuron loss and is independent of stress granules in vivo

This study shows TDP-43 pathology occurs independently of stress granules in motor neurons, challenging existing models of TDP-43 pathogenesis.

Characterising the motif composition and allele length distribution of ZFHX3 GGC repeat expansions in amyotrophic lateral sclerosis

This study examines ZFHX3 GGC repeat expansions in ALS and finds no association with disease risk, but identifies diverse repeat motif compositions.

A region-delineated snRNA-seq atlas of mouse spinal cord across lifespan resolves the interaction of normative aging programs with SOD1-G93A ALS

This study creates a lifespan snRNA-seq atlas of mouse spinal cord, revealing how aging and SOD1-G93A ALS interact regionally and cell-type specifically.