A5083287368- Amyotrophic Lateral Sclerosis Research
- Neurogenetic and Muscular Disorders Research
- Genetic Neurodegenerative Diseases
- RNA Research and Splicing
- Prion Diseases and Protein Misfolding
- Mitochondrial Function and Pathology
- Neuroinflammation and Neurodegeneration Mechanisms
- Parkinson's Disease Mechanisms and Treatments
- Nerve injury and regeneration
- Muscle Physiology and Disorders
- Synthetic Organic Chemistry Methods
- Biochemical Acid Research Studies
- Sirtuins and Resveratrol in Medicine
- Endoplasmic Reticulum Stress and Disease
- Ion channel regulation and function
- Pluripotent Stem Cells Research
- Cholinesterase and Neurodegenerative Diseases
- RNA Interference and Gene Delivery
- RNA regulation and disease
- CRISPR and Genetic Engineering
John Radcliffe Hospital
2017-2025
University of Oxford
2017-2025
An expanded hexanucleotide repeat in a noncoding region of the C9orf72 gene is major cause amyotrophic lateral sclerosis (ALS), accounting for up to 40% familial cases and 7% sporadic ALS European populations. We have generated induced pluripotent stem cells (iPSCs) from fibroblasts patients carrying expansions, differentiated these functional motor cortical neurons, performed an extensive phenotypic characterization. In iPSC-derived decreased cell survival correlated with dysfunction Ca(2+)...
Mislocalization of the predominantly nuclear RNA/DNA binding protein, TDP-43, occurs in motor neurons ~95% amyotrophic lateral sclerosis (ALS) patients, but contribution axonal TDP-43 to this neurodegenerative disease is unclear. Here, we show accumulation intra-muscular nerves from ALS patients and axons human iPSC-derived patient, as well neuromuscular junctions (NMJs) a mislocalization mouse model. In axons, hyper-phosphorylated promotes G3BP1-positive ribonucleoprotein (RNP) condensate...
A non-coding hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is most common cause amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), however, precise molecular mechanism by which directs C9ALS/FTD pathogenesis remains unclear. Here, we report a novel disease arising due to interaction C9ORF72 with RAB7L1 GTPase regulate vesicle trafficking. Endogenous between was confirmed human SH-SY5Y neuroblastoma cells. The led haploinsufficiency resulting severely...
TDP-43 dysfunction is common to 97% of amyotrophic lateral sclerosis (ALS) cases, including those with mutations in C9orf72. To investigate how C9ORF72 drive cellular pathology ALS and identify convergent mechanisms between TARDBP mutations, we analyzed motor neurons (MNs) derived from induced pluripotent stem cells (iPSCs) patients ALS. iPSC-MNs have higher Ca2+ release after depolarization, delayed recovery baseline glutamate stimulation, lower levels calbindin compared CRISPR/Cas9...
Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, with additional pathophysiological involvement of non-neuronal cells such as microglia. The commonest ALS-associated genetic variant hexanucleotide repeat expansion (HRE) mutation in C9orf72 . Here, we study its consequences for microglial function using human iPSC-derived By RNA-sequencing, identify enrichment pathways associated immune cell activation and...
Abstract The G4C2 hexanucleotide repeat expansion (HRE) in C9orf72 is the commonest cause of familial amyotrophic lateral sclerosis (ALS). A number different methods have been used to generate isogenic control lines using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and non-homologous end-joining by deleting region, with risk creating indels genomic instability. In this study, we demonstrate complete correction an induced pluripotent stem cell (iPSC) line derived...
An intronic G4C2 repeat expansion in the C9ORF72 gene is major known cause for Amyotrophic Lateral Sclerosis (ALS), with current evidence both, loss of function and pathological gain disease mechanisms. We screened 96 200 small molecules patient iPS neurons modulation nuclear RNA foci identified 82 validated hits, including Brd4 inhibitor JQ1 as well novel analogs Spliceostatin-A, a modulator SF3B1, branch point binding protein U2-snRNP. Spliceosome by these SF3B1 targeted compounds recruits...
Abstract Motor neuron diseases such as amyotrophic lateral sclerosis are primarily characterized by motor degeneration with additional involvement of non-neuronal cells, in particular, microglia. In previous work, we have established protocols for the differentiation iPSC-derived spinal neurons and Here, combine both cell lineages establish a novel co-culture microglia, which is compatible identity function. Co-cultured microglia express key markers transcriptomically resemble primary human...
TDP-43 pathology is a key feature of amyotrophic lateral sclerosis (ALS), but the mechanisms linking to altered cellular function and neurodegeneration remain unclear. We have recently described mouse model in which human wild-type or mutant are expressed at low levels where stress granule formation robust phenotype TDP-43M337V/− expressing cells. In present study we use this investigate functional connectivity primary motor neurons under resting conditions response oxidative stress. The...
Arginine-rich dipeptide repeat proteins (R-DPRs), abnormal translational products of a GGGGCC hexanucleotide expansion in C9ORF72 , play critical role -related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the most common genetic form disorders (c9ALS/FTD). R-DPRs liquid condensates vitro, induce stress granule formation cultured cells, aggregate, sometimes coaggregate with TDP-43 postmortem tissue from patients c9ALS/FTD. However, how these processes are regulated...
To understand the relative contributions of 5ʹ UTR elements to translation, we performed a comprehensive analysis upstream open reading frames (uORFs) across representative UTR. We selected neurotrophin BDNF (Brain derived neurotrophic factor) as an exemplar upregulation this protein is potential therapeutic approach for plethora neurodevelopmental, neurodegenerative, and neuropsychiatric disorder indications. Predicted uORFs were identified in 14 out 17 RefSeq transcript isoforms,...
Induced pluripotent stem cell (iPSC)-derived motor neurons (MNs) from patients with amyotrophic lateral sclerosis (ALS) and the C9ORF72 hexanucleotide repeat expansion (HRE) have multiple cellular phenotypes, but which of these accurately reflect biology underlying cell-specific vulnerability ALS is uncertain. We therefore compared phenotypes due to HRE in MNs sensory (SNs), are relatively spared ALS. The iPSC models were able partially reproduce differential gene expression seen between...
Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system with complex determinants, including genetic and non-genetic factors. A key pathological signature ALS cytoplasmic mislocalization aggregation TDP-43 in affected neurons, which found 97% cases. Recent reports have shown that mitochondrial dysfunction plays significant role neuron degeneration ALS, modulates several transcripts. In this study, we used induced pluripotent stem cell-derived neurons...
The GGGGCC hexanucleotide repeat expansion mutation in the chromosome 9 open reading frame 72 (C9orf72) gene is a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). In this study, we demonstrate that zinc finger (ZF) transcriptional regulator Yin Yang 1 (YY1) binds to promoter region planar cell polarity Fuzzy regulate its transcription. We show YY1 interacts with RNA via ZF interaction compromises binding FuzzyYY1 sites, resulting downregulation...
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that currently lacks effective therapy. Given the heterogeneity of clinical and molecular profiles ALS patients, personalized diagnostics pathological characterization represent powerful strategy to optimize patient stratification, thereby enabling treatment. Immortalized lymphocytes from sporadic genetic patients recapitulate some hallmarks disease, facilitating fundamental task drug screening. However,...
Abstract The G4C2 hexanucleotide repeat expansion (HRE) in C9orf72 is the commonest cause of familial amyotrophic lateral sclerosis (ALS). A number different methods have been used to generate isogenic control lines using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 and non-homologous end-joining (NHEJ) by deleting region with risk creating indels genomic instability. In this study we demonstrate complete correction an induced pluripotent stem cell (iPSC) line...