Adrian M. Isaacs

Altered neuronal start codon stringency favors cap-independent repeat-associated non-AUG translation

The paper shows that neurons prefer cap-independent RAN translation from specific repeats, linked to altered start codon stringency and eIF1 redistribution.

Scalable human neuronal models of tauopathy producing endogenous seed-competent 4R tau

This paper develops a scalable human neuronal model of 4R tauopathy with endogenous seed-competent tau for drug discovery.

The ALS- and FTD-associated proteins Annexin A11 and CHMP2B act sequentially in membrane repair

The paper investigates the sequential roles of Annexin A11 and CHMP2B in membrane repair, showing Annexins act first to seal damage while ESCRT-III removes damaged membranes.

Metformin promotes broad neuroprotection and proteostatic resilience via rngo/DDI2 stabilisation

This paper shows metformin protects neurons by stabilizing rngo/DDI2, enhancing proteostasis and reducing toxicity in multiple neurodegenerative models.

U7 small nuclear RNA splice-switching therapeutics for STMN2 and UNC13A in Amyotrophic Lateral Sclerosis

The paper develops U7 snRNA therapeutics to correct TDP-43-dependent mis-splicing in ALS, restoring gene expression and neuronal function in human iPSC-derived neurons.

CANVAS causing AAGGG repeat expansions cause tissue-specific reduction in RFC1 expression and increase sensitivity to DNA damage

CRISPR/Cas9-mediated generation of a de novo C9ORF72 knock-in isogenic iPSC cell bank to model ALS and FTD

The paper generates isogenic iPSC lines with a C9ORF72 G4C2 repeat expansion to model ALS and FTD, showing both loss- and gain-of-function pathologies.

The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases uncovers cholesterol as a regulator of astrocyte reactivity impaired by ApoE4

The paper introduces the Neurolipid Atlas, a lipidomics resource for neurodegenerative diseases, revealing that ApoE4 impairs astrocyte reactivity by promoting cholesterol ester accumulation.

C9orf72 polyGA knock-in mice exhibit mild motor and proteomic changes consistent with ALS/FTD

This study creates (GA)400 knock-in mice to model C9orf72 polyGA expression, finding mild motor dysfunction and proteomic changes in the spinal cord.

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.

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.

Generation of C9orf72 repeat knock-in iPSC lines for modelling ALS and FTD

The paper describes the generation and validation of C9orf72 repeat expansion knock-in iPSC lines for ALS and FTD research, showing they differentiate into neurons and display disease-related pathologies.

Generation of C9orf72h370 mice, an intron 1 humanised C9orf72 repeat-expansion knock-in model

The paper generates a mouse model with a humanised C9orf72 repeat expansion to study ALS and FTD, and demonstrates a method for creating such repeat expansions in genomic sequences.

Dual-targeting CRISPR-CasRx reduces C9orf72 ALS/FTD sense and antisense repeat RNAs in vitro and in vivo

This study demonstrates that CRISPR-CasRx reduces C9orf72 repeat RNAs and DPRs in vitro and in vivo, suggesting its therapeutic potential for ALS/FTD.

A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer's disease models

This study shows that increasing pyruvate import in neurons rescues dementia-like phenotypes in fly models by clearing toxic protein deposits.

PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons

The paper generates C9orf72 DPR knock-in mice and identifies an extracellular matrix signature in C9ALS/FTD that is conserved across species and protected by TGF-β1 and COL6A1.

G2C4 targeting antisense oligonucleotides potently mitigate TDP-43 dysfunction in C9orf72 ALS/FTD human neurons

This study shows that targeting G2C4 antisense repeat RNA, not G4C2 sense RNA, mitigates TDP-43 dysfunction in C9orf72 ALS/FTD patient neurons, explaining the failure of previous G4C2 ASO clinical trials.

Genome-wide RNA binding analysis of C9orf72 poly(PR) dipeptides

The paper identifies genome-wide RNA binding sites of poly(PR) dipeptides and shows preferential binding to GAAGA-containing RNAs, suggesting a role in neurodegeneration.

Immune reactivity to neurofilaments and dipeptide repeats in ALS progression

The paper tests antibody and immune-complex responses to neurofilaments and dipeptide-repeats as biomarkers for ALS progression and stratification.

FUS ALS-causative mutations impact FUS autoregulation and the processing of RNA-binding proteins through intron retention

This study identifies how ALS-causative FUS mutations disrupt RNA processing and autoregulation, with implications for broader ALS genetic interactions.

Quantitative analysis of cryptic splicing associated with TDP-43 depletion

The paper quantifies cryptic exon inclusion in TDP-43 depleted datasets and shows they are bound by TDP-43 and not linked to FUS, with implications for ALS/FTD pathogenesis.