Biomedical subjects

Sarah J Tabrizi

Publications and source records attributed to Sarah J Tabrizi.

7 recordsLinked to original sources

PubMed2025

Antisense oligonucleotide-mediated MSH3 suppression reduces somatic CAG repeat expansion in Huntington's disease iPSC-derived striatal neurons.

Expanded CAG alleles in the huntingtin (HTT) gene that cause the neurodegenerative disorder Huntington's disease (HD) are genetically unstable and continue to expand somatically throughout life, driving HD onset and progression. MSH3, a DNA mismatch repair protein, modifies HD onset and progression by driving this somatic CAG repeat expansion process. MSH3 is relatively tolerant of loss-of-function variation in humans, making it a potential therapeutic target. Here, we show that an MSH3-targeting antisense oligonucleotide (ASO) effectively engaged with its RNA target in induced pluripotent stem cell (iPSC)-derived striatal neurons obtained from a patient with HD carrying 125 HTT CAG repeats (the 125 CAG iPSC line). ASO treatment led to a dose-dependent reduction of MSH3 and subsequent stalling of CAG repeat expansion in these striatal neurons. Bulk RNA sequencing revealed a safe profile for MSH3 reduction, even when reduced by >95%. Maximal knockdown of MSH3 also effectively slowed CAG repeat expansion in striatal neurons with an otherwise accelerated expansion rate, derived from the 125 CAG iPSC line where FAN1 was knocked out by CRISPR-Cas9 editing. Last, we created a knock-in mouse model expressing the human MSH3 gene and demonstrated effective in vivo reduction in human MSH3 after ASO treatment. Our study shows that ASO-mediated MSH3 reduction can prevent HTT CAG repeat expansion in HD 125 CAG iPSC-derived striatal neurons, highlighting the therapeutic potential of this approach.

Huntington Disease↗

PubMed2025

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

Induced pluripotent stem cell (iPSC) models are powerful tools for neurodegenerative disease modelling, as they allow mechanistic studies in a human genetic environment and they can be differentiated into a range of neuronal and non-neuronal cells. However, these models come with inherent challenges due to line-to-line and clonal variability. To combat this issue, the iPSC Neurodegenerative Disease Initiative (iNDI) has generated an iPSC repository using a single clonal reference line, KOLF2.1J, into which disease-causing mutations and revertants are introduced via gene editing. Here we describe the generation and validation of lines carrying the most common causative mutation for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a repeat expansion in the C9orf72 gene, for the iNDI collection of neurodegenerative iPSC models. We demonstrate that these C9orf72 knock-in lines differentiate efficiently into neurons and display characteristic C9orf72-associated pathologies, including reduced C9orf72 levels and the presence of dipeptide repeat proteins (DPRs) and RNA foci, which increase in abundance over time in culture. These pathologies are not present in revertant cells lacking the repeat expansion. These repeat expansion and revertant cell lines are now available to academic and for-profit institutions through the JAX iPS cell repository and will help to facilitate and standardise iPSC-based ALS/FTD research.

Journal Article↗

PubMed2003

Models of Parkinson's disease.

Parkinson's disease (PD) is a heterogenous disease likely to be caused by more than one specific aetiological factor. In rare familial cases of PD with similar clinical features to the idiopathic form of the disease, the underlying genetic cause has been identified. These PD-associated genes have been manipulated to create animal and cell culture models of the disease that have helped to further our understanding of the pathogenesis of PD, particularly concerning causes of the selective loss of dopaminergic neurons at the molecular level. In addition, these models will aid the future development of rational therapeutic strategies. This study briefly reviews toxin-induced models and the genetics of PD. It focuses on recently developed animal models of PD, as well as in vitro approaches to model the disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2003

Prion diseases.

Prion diseases are incurable neurodegenerative conditions affecting both animals and humans. They may be sporadic, infectious, or inherited in origin. Human prion diseases include Creutzfeldt-Jakob desease (CJD), Gerstmann-Straussler-Scheinker disease, kuru, and fatal familial insomnia. The appearance of variant CJD, and the demonstration that is caused by strains indistinguishable from bovine spongiform encephalopathy (BSE) in cattle, has led to the threat of a major epidemic of human prion disease in the UK and other countries where widespread dietary exposure to bovine prions has occurred. This article reviews the history and epidemiology of these diseases, and then focuses on important areas of current research in human prion disorders.

Animals↗

PubMed2003

Mouse models as a tool for understanding neurodegenerative diseases.

PURPOSE OF REVIEW: The purpose of this review is to present recent advances in the both the creation and the use of mouse models of human neurodegenerative disease. We briefly touch on the technologies used to make these models, and then focus on recent results from new models. We discuss why such models are useful when they do - and do not - mimic the human disorder. RECENT FINDINGS: The numbers of mouse models are increasing dramatically and are starting to yield important results for human disease. We present a selection of new and important models and the results of recent investigations of these animals. SUMMARY: An accepted protocol when studying any form of human neurodegenerative disease is to investigate the genetics, pathology, neurophysiology, response to therapeutics, etc., of the disorder in the mouse. This approach is clearly bearing fruit for our understanding and treatment of human neurodegeneration.

Animals↗

PubMed2002

Mouse models for neurological disease.

The mouse has many advantages over human beings for the study of genetics, including the unique property that genetic manipulation can be routinely carried out in the mouse genome. Most importantly, mice and human beings share the same mammalian genes, have many similar biochemical pathways, and have the same diseases. In the minority of cases where these features do not apply, we can still often gain new insights into mouse and human biology. In addition to existing mouse models, several major programmes have been set up to generate new mouse models of disease. Alongside these efforts are new initiatives for the clinical, behavioural, and physiological testing of mice. Molecular genetics has had a major influence on our understanding of the causes of neurological disorders in human beings, and much of this has come from work in mice.

Animals↗

PubMedDate not supplied

Idiopathic intimal hyperplasia of small arteries and arterioles affecting intestines and myocardium.

We report the case of a 52-year-old woman dying from a noninflammatory, occlusive vasculopathy. Histology showed marked intimal hyperplasia of small arteries of the intestines and myocardium with subsequent infarction of myocardium, large intestine and gallbladder. A comprehensive work up including laboratory studies, clinical investigations and postmortem failed to assign this condition to any of the known vascular diseases.

Arterioles↗