"My lab integrates genetics and iPSC models to investigate the mechanisms that underlie risk for different tauopathies, with the goal of identifying new targets for therapeutic development." Kathryn Bowles
UK DRI Group Leader
Dr Kathryn Bowles' primary interest is in understanding the genetic and mechanistic biology underlying tauopathy. She completed her PhD at Cardiff University in Prof Lesley Jones' lab, before moving to the Icahn School of Medicine at Mount Sinai in New York, where she joined Prof Alison Goate's lab as a postdoctoral fellow. She then joined the University of Edinburgh UK DRI to start her own lab in 2022, where her work is supported by the BrightFocus Foundation and the Rainwater Charitable Foundation. Dr Bowles' lab integrates functional genomics, biochemistry and iPSC organoid models to investigate the regulation of MAPT expression, function and splicing, and how these processes contribute to Alzheimer's disease, frontotemporal dementia, Parkinson's disease and other tauopathies.
1. At a glance
Tau is implicated in many different neurodegenerative diseases. The protein normally helps provide structural support to nerve cells in the brain – acting as a type of scaffolding. In Alzheimer’s, it becomes misfolded and accumulates in clumps, or tangles, and is implicated strongly with the symptoms of cognitive decline that are associated with the disease.
The gene that codes for the tau protein is large and complex, and varies greatly among different populations across the world. Tau behaves differently in different diseases, and can accumulate in distinct cell types and structures.
Dr Bowles and her team are using cellular models of tau pathology, to try and unpick what happens within the cell when there is a mutation in the tau gene. Advancing the fundamental understanding of tau in this way would provide a important piece of the puzzle that could lead to effective new treatments targeting the diseases involving tau.
2. Scientific goals
Frontotemporal dementia (FTD) encompasses a spectrum of disorders affecting behaviour and speech, and accounts up to 20% of dementia cases under age 65. Mutations in the microtubule-associated protein tau (MAPT) gene have been identified in up to 38% of familial FTD cases (FTD-tau). iPSC-based models derived from patients with MAPT mutations show promise for studying early molecular mechanisms underlying tauopathy and recapitulate many disease-associated phenotypes observed in human brain. This UK DRI programme led by Dr Kathryn Bowles employs iPSC modelling to investigate the early molecular mechanisms underlying FTD-tau.
In previous work, Dr Bowles and team characterized a 3D cerebral organoid model of FTD-tau, with the goal of identifying temporal changes preceding and leading to neurodegeneration. They found that this model exhibited progressive accumulation of total and phosphorylated tau, and later specific loss of glutamatergic neurons. The team are now investigating the role of glutamate signalling in synaptic function and neuronal survival in an organoid model of FTD.
The 17q21.31 “MAPT” locus spans a 1.5Mb region of high linkage disequilibrium caused by a 970kb inversion, which confers two distinct haplotypes; H1, and the inverted H2, which is almost absent in East and South Asian populations. The Bowles lab aims to investigate and fully characterize how structural variation at the 17q21.31 locus contributes to disease risk across different genetic ancestries and to uncover the H1-specific mechanisms contributing to disease risk.
The 4R isoform of tau is important in FTD and progressive supranuclear palsy (PSP) pathology, but it is challenging to model using iPSC systems, as neurons derived from these cells express very low levels of 4R tau. The Bowles lab have developed a panel of iPSC lines, derived from donors with specific MAPT mutations, that express significantly more 4R tau than controls. The team are using these iPSC lines to model the early changes occurring in PSP/FTD brain due to the increased expression of 4R Tau, in order to better understand the functional impact of this isoform in multiple cell-types, with a goal to inform future therapeutic development.
Main objectives and research goals:
- Use iPSC modelling to investigate the early molecular mechanisms underlying tauopathy.
- Investigate the role of glutamate signalling in synaptic function and neuronal survival in a model of FTD.
- Investigate and characterise how structural variations in the MAPT gene contribute to disease risk across different populations
3. Team members
Dr Kathryn Newton (Senior Research Technician)
Dr Filipa Henderson-Sousa (Postdoctoral Researcher)
Lois Keavey (Research Assistant)
Tauopathies, Parkinson’s disease, Genetics, 17q21.31, MAPT, Neurodegeneration,
iPSCs, Organoids, CRISPR/Cas9, Transcriptomics, Single cell sequencing, Human tissues, Biochemistry, Genetics
6. Key publications
Bowles, KR., Pugh, DA., Liu, Y., Patel, T., Renton, AE., Bandres-Ciga, S., Gan-Or, Z., Heutink, P., Siitonen, A., Bertelsen, S., Cherry, JD., Karch, CM., Frucht, SJ., Kopell, BH., Peter, I., Park, YJ., International Parkinson’s Diseases Genetics Consortium., Charney, A., Raj, T., Crary, JF & Goate, AM. 17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes. 2022 Molecular Neurodegeneration 17;48:1-21
Bowles, KR., Pugh, DA., Jadow, BM., Farrell, K., Cherry, JD., Raj, T., Crary, JF and Goate, AM. Dysregulation of coordinated MAPT exon 2 and exon 10 splicing underlies Tau pathology in AD and PSP. 2022. Acta Neuropathologica, 143(2): 225-243. doi: 10.1007/s00401-021-02392-2
Bowles, KR., Silva, MC., Whitney, K., Bertucci, T., Berlind, JE., Lai, JD., Garza, JC., Boles, NC., Mahali, S., Strang, KH., Marsh, JA., Chen, C., Pugh, DA., Liu, Y., Gordon, RE., Goderie, SK., Chowdhury, R., Lotz, S., Lane, K., Crary, JF., Haggarty, SJ., Karch, CM., Ichida, JK., Goate, AM and Temple, S. ELAVL4 expression, aberrant splicing and glutamate dysfunction precede neuron loss in cerebral organoids with MAPT mutation. 2021 Cell 19;184(17):4547-4563
Karch, CM., Kao, AW., Karydas, A., Onanuga, K., Martinez, R., Argouarch, A., Wang, C., Huang, C., Sohn, PD., Bowles, KR., Spina, S., Silva, CM., Marsh, J., Hsu, S., Pugh, DA.,Ghoshal, N., Norton, J., Huang, Y., Lee, SE., Theofilas, P., Grinberg, LT., Moreno, F., McIlroy, K., Boeve, BF., Cairns, NJ., Crary, JF., Haggarty, SJ., Ichida, JK., Kosik, KS., Miller, BL., Gan, L., Goate, AM., Temple, S & Tau Consortium Stem Cell Group. A comprehensive resource for induced pluripotent stem cells from patients with primary Tauopathies. 2019. Stem Cell Reports, 13, 939-955
Bowles, KR., TCW, J., Qian, L., Jadow, BM. & Goate, AM. Reduced variability of neural progenitor cells and improved purity of neuronal cultures using magnetic activated cell sorting. 2019. PLoS ONE, 14(4): e0216312