A5031012251- Amyotrophic Lateral Sclerosis Research
- Neurogenetic and Muscular Disorders Research
- Alzheimer's disease research and treatments
- RNA Research and Splicing
- Parkinson's Disease Mechanisms and Treatments
- Neuroinflammation and Neurodegeneration Mechanisms
- Prion Diseases and Protein Misfolding
- Autophagy in Disease and Therapy
- Neurological diseases and metabolism
- Cholinesterase and Neurodegenerative Diseases
- Pluripotent Stem Cells Research
- Mitochondrial Function and Pathology
- CRISPR and Genetic Engineering
- Cancer-related gene regulation
- Dementia and Cognitive Impairment Research
- Extracellular vesicles in disease
- Histone Deacetylase Inhibitors Research
- Neuroscience and Neuropharmacology Research
- Nerve injury and regeneration
- Neurogenesis and neuroplasticity mechanisms
- Genetic Neurodegenerative Diseases
- RNA regulation and disease
- Tryptophan and brain disorders
- Biomedical Ethics and Regulation
- Functional Brain Connectivity Studies
University of Sheffield
2016-2025
Neuroscience Institute
2024
Nationwide Children's Hospital
2012-2017
The Ohio State University
2015
A GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). encodes two protein isoforms unclear function. Reduced levels expression have been reported C9ALS/FTD patients, although haploinsufficiency has proposed to contribute C9ALS/FTD, its significance not yet clear. Here, we report that interacts with Rab1a Unc-51-like kinase 1 (ULK1) autophagy initiation complex. As a effector,...
Significance Direct conversion is a recently established method to generate neuronal progenitor cells (NPCs) from skin fibroblasts in fast and efficient manner. In this study, we show that can be used model neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Because the origin of ALS mainly sporadic with unknown cause, methods disease are urgently needed. The produced NPCs differentiated into astrocytes, which involved motor neuron death ALS. Strikingly, skin-derived...
Spinal muscular atrophy (SMA) is the most frequent lethal genetic neurodegenerative disorder in infants. The disease caused by low abundance of survival motor neuron (SMN) protein leading to degeneration and progressive paralysis. We previously demonstrated that a single intravenous injection (IV) self-complementary adeno-associated virus-9 carrying human SMN cDNA (scAAV9-SMN) resulted widespread transgene expression spinal cord neurons SMA mice as well nonhuman primates complete rescue...
Amyotrophic lateral sclerosis (ALS) is a complex disease that leads to motor neuron death. Despite heritability estimates of 52%, genome-wide association studies (GWASs) have discovered relatively few loci. We developed machine learning approach called RefMap, which integrates functional genomics with GWAS summary statistics for gene discovery. With transcriptomic and epigenetic profiling neurons derived from induced pluripotent stem cells (iPSCs), RefMap identified 690 ALS-associated genes...
Amyotrophic lateral sclerosis (ALS), a common late-onset neurodegenerative disease, is associated with fronto-temporal dementia (FTD) in 3-10% of patients. A mutation CHMP2B was recently identified Danish pedigree autosomal dominant FTD. Subsequently, two unrelated patients familial ALS, one whom also showed features FTD, were shown to carry missense mutations CHMP2B. The initial aim this study determine whether contribute more broadly ALS pathogenesis.Sequencing 433 cases from the North...
The cellular pathways of motor neuronal injury have been investigated in the SOD1 G93A murine model familial amyotrophic lateral sclerosis (ALS) using laser-capture microdissection and microarray analysis. advantages this study include following: analysis changes specifically neurons (MNs), while still detecting effects interactions with neighboring cells; ability to profile during disease progression, an approach not possible human ALS; use transgenic mice bred on a homogeneous genetic...
Mutations in superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (ALS) resulting progressive motor neuron death through one or more acquired toxicities. Involvement of wild-type SOD1 has been sporadic ALS, as misfolded reported affected tissues patients and toxicity astrocytes derived from ALS neurons be reduced by lowering the synthesis SOD1. We now report slowed disease onset progression two mouse models following therapeutic delivery using a single...
Amyotrophic lateral sclerosis is a neurodegenerative disease in which death of motoneurons leads to progressive failure the neuromuscular system resulting frequently within 2–3 years symptom onset. Focal onset and propagation symptoms contiguous motoneuron groups striking feature human progression. Recent work, using mutant superoxide dismutase 1 murine models vitro culture systems has indicated that astrocytes are likely contribute injury However, basis this astrocyte toxicity and/or...
Significance Amyotrophic lateral sclerosis can be caused by a mutation in superoxide dismutase. Ubiquitously expressed, disease mechanism involves damage within motor neurons (whose degeneration is responsible for progressive paralysis) and glia. By combining ribosome affinity purification from each of three cell types, temporal cascade identified that initiates neurons, with subsequent glia driving propagation. Mutant-dependent to which are shown express very low levels endoplasmic...
Significance Oligodendrocytes have been implicated in disease pathology amyotrophic lateral sclerosis (ALS) using transgenic mouse models. To date there is no human coculture system available to investigate oligodendrocyte involvement motor neuron (MN) death ALS. Our data highlight that oligodendrocytes derived from patients with familial and sporadic ALS induced pluripotent stem cells neural progenitor play an active role MN death. Oligodendrocyte toxicity mediated through soluble factors...
Abstract Hexanucleotide repeat expansions in the C9ORF72 gene are commonest known genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Expression transcripts dipeptide proteins trigger multiple mechanisms neurotoxicity. How get exported from nucleus is unknown. Here, we show that depletion nuclear export adaptor SRSF1 prevents neurodegeneration locomotor deficits a Drosophila model C9ORF72-related disease. This intervention suppresses cell death patient-derived motor...
Aims Loss of nuclear TDP ‐43 characterizes sporadic and most familial forms amyotrophic lateral sclerosis ( ALS ). (encoded by TARDBP ) has multiple roles in RNA processing. We aimed to determine whether (1) splicing dysregulation is present lower motor neurones a neurone‐like cell model; (2) mutations (mt are associated with aberrant using patient‐derived fibroblasts. Methods A ffymetrix exon arrays were used study mRNA expression obtained laser capture microdissection autopsy tissue from...
Sporadic amyotrophic lateral sclerosis (ALS) is a fatal disease with unknown etiology, characterized by progressive loss of motor neurons leading to paralysis and death typically within 3–5 years onset. Recently, there has been remarkable progress in understanding inherited forms ALS which well defined mutations are known cause the disease. Rodent models superoxide dismutase-1 (SOD1) mutation overexpressed recapitulate hallmark signs patients. Early anatomical changes mouse fALS seen...
As clinical evidence supports a negative impact of dysfunctional energy metabolism on the disease progression in amyotrophic lateral sclerosis, it is vital to understand how metabolic pathways are altered and whether they can be restored slow progression. Possible approaches include increasing or rerouting catabolism alternative fuel sources supplement glycolytic mitochondrial such as glycogen, ketone bodies nucleosides. To analyse basis catabolic defect sclerosis we used novel phenotypic...
It is important to understand how the disease process affects metabolic pathways in amyotrophic lateral sclerosis and whether these can be manipulated ameliorate progression. To analyse basis of defect we used a phenotypic profiling approach. Using fibroblasts reprogrammed induced astrocytes from C9orf72 sporadic cases measured production rate reduced nicotinamide adenine dinucleotides (NADH) 91 potential energy substrates simultaneously. Our screening approach identified that have distinct...
Which isoforms of apolipoprotein E (apoE) we inherit determine our risk developing late-onset Alzheimer's Disease (AD), but the mechanism underlying this link is poorly understood. In particular, relevance direct interactions between apoE and amyloid-β (Aβ) remains controversial. Here, single-molecule imaging shows that all associate with Aβ in early stages aggregation then fall away as fibrillation happens. ApoE-Aβ co-aggregates account for ~50% mass diffusible aggregates detected frontal...