ORCID Profile
0000-0001-6691-580X
Current Organisation
University of Oxford
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Publisher: Elsevier BV
Date: 03-2016
Publisher: Elsevier BV
Date: 03-2015
Publisher: Springer Science and Business Media LLC
Date: 24-01-2017
DOI: 10.1038/SREP41188
Abstract: Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, affecting 1% of the population over 65 years characterized clinically by both motor and non-motor symptoms accompanied by the preferential loss of dopamine neurons in the substantia nigra pars compacta. Here, we sequenced the exomes of 244 Parkinson’s patients selected from the Oxford Parkinson’s Disease Centre Discovery Cohort and, after quality control, 228 exomes were available for analyses. The PD patient exomes were compared to 884 control exomes selected from the UK10K datasets. No single non-synonymous (NS) single nucleotide variant (SNV) nor any gene carrying a higher burden of NS SNVs was significantly associated with PD status after multiple-testing correction. However, significant enrichments of genes whose proteins have roles in the extracellular matrix were amongst the top 300 genes with the most significantly associated NS SNVs, while regions associated with PD by a recent Genome Wide Association (GWA) study were enriched in genes containing PD-associated NS SNVs. By examining genes within GWA regions possessing rare PD-associated SNVs, we identified RAD51B . The protein-product of RAD51B interacts with that of its paralogue RAD51 , which is associated with congenital mirror movements phenotypes, a phenotype also comorbid with PD.
Publisher: Springer Science and Business Media LLC
Date: 28-11-2007
Publisher: Informa UK Limited
Date: 04-2012
DOI: 10.4161/AUTO.19496
Publisher: Oxford University Press (OUP)
Date: 11-02-2019
DOI: 10.1093/HMG/DDZ038
Publisher: Elsevier BV
Date: 08-2012
Publisher: Elsevier BV
Date: 2019
Publisher: Springer Science and Business Media LLC
Date: 31-07-2007
Publisher: Springer Science and Business Media LLC
Date: 21-08-2020
DOI: 10.1038/S41467-020-17876-0
Abstract: We describe a human single-nuclei transcriptomic atlas for the substantia nigra (SN), generated by sequencing approximately 17,000 nuclei from matched cortical and SN s les. We show that the common genetic risk for Parkinson’s disease (PD) is associated with dopaminergic neuron (DaN)-specific gene expression, including mitochondrial functioning, protein folding and ubiquitination pathways. We identify a distinct cell type association between PD risk and oligodendrocyte-specific gene expression. Unlike Alzheimer’s disease (AD), we find no association between PD risk and microglia or astrocytes, suggesting that neuroinflammation plays a less causal role in PD than AD. Beyond PD, we find associations between SN DaNs and GABAergic neuron gene expression and multiple neuropsychiatric disorders. Conditional analysis reveals that distinct neuropsychiatric disorders associate with distinct sets of neuron-specific genes but converge onto shared loci within oligodendrocytes and oligodendrocyte precursors. This atlas guides our aetiological understanding by associating SN cell type expression profiles with specific disease risk.
Publisher: Oxford University Press (OUP)
Date: 17-01-2017
DOI: 10.1093/HMG/DDW412
Publisher: The Royal Society
Date: 06-04-2016
Abstract: The Virtual Physiological Human (VPH) project aims to develop integrative, explanatory and predictive computational models (C-Models) as numerical investigational tools to study disease, identify and design effective therapies and provide an in silico platform for drug screening. Ultimately, these models rely on the analysis and integration of experimental data. As such, the success of VPH depends on the availability of physiologically realistic experimental models (E-Models) of human organ function that can be parametrized to test the numerical models. Here, the current state of suitable E-models, ranging from in vitro non-human cell organelles to in vivo human organ systems, is discussed. Specifically, challenges and recent progress in improving the physiological realism of E-models that may benefit the VPH project are highlighted and discussed using ex les from the field of research on cardiovascular disease, musculoskeletal disorders, diabetes and Parkinson's disease.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 19-05-2021
DOI: 10.1126/SCITRANSLMED.AAW1564
Abstract: Viral vectors restore dopamine transporter function and ameliorate neuropathology in iPSC-derived neurons and a mouse model of infantile parkinsonism.
Publisher: Cold Spring Harbor Laboratory
Date: 02-03-2023
DOI: 10.1101/2023.03.01.530566
Abstract: Understanding medium spiny neuron (MSN) physiology is essential to understand motor impairments in Parkinson’s disease (PD) given the architecture of the basal ganglia. Here, we developed a custom three-chamber microfluidic platform and established a cortico-striato-nigral microcircuit recapitulating the striatal presynaptic triad in vitro using induced pluripotent stem cell (iPSC)-derived neurons. We found that, although cortical glutamatergic projections facilitated MSN synaptic activity, dopaminergic transmission was essential for excitability maturation of MSNs in vitro . Replacement of wild-type iPSC-dopamine neurons (iPSC-DaNs) in the striatal microcircuit with those carrying the PD-related GBA-N370S mutation induced early hyperexcitability in iPSC-MSNs through reduction of voltage-gated sodium and potassium intrinsic currents. Such deficits were resolved in aged cultures or with antagonism of protein kinase A activity in nigrostriatal iPSC-DaNs. Hence, our results highlight the unique utility of modelling striatal neurons in a modular and highly physiological circuit which is essential to reveal mechanistic insights of the loss of electrical functional integrity in the striata of GBA1 PD patients.
Publisher: Springer Science and Business Media LLC
Date: 14-04-2011
DOI: 10.1038/GT.2011.45
Abstract: Novel gene-based therapies for disease will depend in many cases on long-term persistent transgene expression. To develop gene therapy strategies for Friedreich's ataxia (FRDA), we have examined the persistence of transgene expression in the brain in vivo provided by the entire 135 kb FXN genomic DNA locus delivered as an infectious bacterial artificial chromosome (iBAC) herpes simplex virus type 1 (HSV-1)-based vector injected in the adult mouse cerebellum. We constructed genomic DNA-reporter fusion vectors carrying a complete 135 kb FXN genomic locus with an insertion of the Escherichia coli lacZ gene at the ATG start codon (iBAC-FXN-lacZ). SHSY5Y human neuroblastoma cells transduced by iBAC-FXN-lacZ showed high efficiency of vector delivery and LacZ expression. Direct intracranial injection of iBAC-FXN-lacZ into the adult mouse cerebellum resulted in a large number of easily detectable transduced cells, with LacZ expression driven by the FXN genomic locus, which persisted for at least 75 days. Green fluorescent protein expression driven from the same vector but by the strong HSV-1 IE4/5 promoter was transient. Our data demonstrate for the first time sustained transgene expression in vivo by infectious delivery of a genomic DNA locus >100 kb in size. Such an approach may be suitable for gene rescue strategies in neurological disease, such as FRDA.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Richard Wade-Martins.