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Dr Rohan de Silva
1 Wakefield Street
  • Reader in Neuroscience
  • Molecular Neuroscience
  • Institute of Neurology
  • Faculty of Brain Sciences
Research Groups
Research Themes
Research Summary
In the last two decades, the discovery of inherited gene defects in the familial forms of Alzheimers disease (AD), Parkinsons disease (PD) and frontotemporal dementias with parkinsonism (FTDP) and the study of the functions of their proteins within the context of the healthy and diseased neural cells has resulted in great leaps in our understanding of the pathogenic processes involved in these disorders. My research interest involves the tau (MAPT) and alpha-synuclein (SNCA) genes and their proteins in neurodegeneration. MAPT, which is mutated in familial FTDP liked to chromosome 17 (FTDP-17), codes for tau, a neuronal microtubule binding protein. Insoluble fibrillar aggregates of tau (tangle pathology) characterise the intraneuronal pathological inclusions that are hallmarks of the group of related neurological disorders called the tauopathies. These include AD and FTDP-17, and the parkinsonian disorder, progressive supranuclear palsy (PSP). MAPT mutations affect either the microtubule-binding capacity, fibrillogenicity or the production of tau protein isoforms. In addition to mutations in genes such as SNCA and MAPT causing the inherited forms of PD and FTDP-17, respectively, it has been shown that common genetic variation in these genes modulate risk in the sporadic forms of these and related diseases. For long it has been recognised that the H1 haplotype of MAPT increases risk of PSP and corticobasal degeneration (CBD). We have been investigating the functional basis of this association and identified H1c, a sub-haplotype of H1, that accounts for the increased risk. We also observed that individuals with the H1c haplotype have higher MAPT transcription and production of the more fibrillogenic four-repeat isoforms of tau (4R-tau). As part of and MRC-funded 5-year research grant and a PhD studentship from the Alzheimers Research Trust (ART), we are currently investigating the regional expression of tau isoforms in PSP brains, depending on MAPT genotype (to understand if differences will explain the regional variations in vulnerability of neuronal populations) and regulation of MAPT transcription and splicing and the influence of the common genetic polymorphisms in MAPT, using cell culture models and proteomics approaches. We are coupling this work with array-based genomewide association and expression studies. In addition to genetic analysis and gene expression studies in postmortem brain, we are also investigating cellular aspects of alpha-synuclein function/dysfunction using cell culture models. We have potentially important evidence linking alpha-synuclein to mitochondrial function and endoplasmic reticulum stress responses.
01-AUG-2007 Reader in Neuroscience UCL Institute of Neurology/Reta Lila Weston Institute UCL, United Kingdom
Academic Background
1991 DPhil Doctor of Philosophy – Biochemistry and Molecular Biology University of Oxford
1987 LIC Licentiate – Chemistry Universitat Bern
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