About the Project
Dementia causes enormous personal hardship and costs the UK ~£23 billion every year. The second most common form is Frontotemporal lobar degeneration (FTLD). About 40% of FTLD cases have genetic causes, with >8% involving abnormal intronic GGGGCC hexanucleotide repeat expansions in the C9orf72 gene which can additionally cause motor neuron disease. These pathological expansions are actively transcribed and, via bidirectional repeat-associated non-ATG (RAN) translation, generate 5 different aggregate-forming dipeptide repeat proteins (DPRs).
This project will gain new understanding of this type of FTLD by unravelling neurodegenerative pathomechanisms of DRPs through using interdisciplinary approaches. We will focus on the hypothesis that toxicity is caused by DRP structure, comparable to amyloid plaques in Alzheimer’s disease. The project will capitalise on the complementary expertises of the three supervisors, and a readily available, unique set of 4 GFP-tagged repeat constructs with pathologically relevant repeat numbers generated by SPB.
The detailed aims and outcomes are:
1: To generate purified DRPs and perform biochemical and biophysical analyses, in order to understand the reasons for their toxicity and identify useful therapeutic strategies which will benefit patients and their families.
2: To generate transgenic Drosophila fly stocks to obtain primary neurons expressing the four DRPs. We will use powerful fly genetics and well established cell biological approaches to identify the neuronal death pathway (apoptosis, necrosis, autophagy), to then block cell death and carry out a detailed analysis of the DRP pathomechanisms upstream.
3: There is substantial proof-of-principle for the use and translational potential of Drosophila neurons. To validate identified DRP pathomechanisms in mammalian contexts, we will carry out complementary experiments using well established DRP models in SH-SY5Y cells and inducible neuronal cell lines.
https://www.research.manchester.ac.uk/portal/en/persons/stuart-pickeringbrown(31b373ef-d615-47b8-b456-19a8e8ae2bb5).html
http://www.manchester.ac.uk/research/Andreas.prokop/
http://www.chemistry.manchester.ac.uk/people/staff/profile/?ea=andrew.doig
References
Mizielinska S, Grönke S, Niccoli T, Ridler CE, Clayton EL, Devoy A, Moens T, Norona FE, Woollacott IO, Pietrzyk J, Cleverley K, Nicoll AJ, Pickering-Brown S, Dols J, Cabecinha M, Hendrich O, Fratta P, Fisher EM, Partridge L, Isaacs AM. C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science. 2014 Sep 5;345(6201):1192-4.
Beaven, R., Dzhindzhev, N. S., Qu, Y., Hahn, I., Dajas-Bailador, F., Ohkura, H., Prokop, A. (2015). Drosophila CLIP-190 and mammalian CLIP-170 display reduced microtubule plus end association in the nervous system. Mol Biol Cell 26, 1491-1508
Voelzmann, A., Okenve-Ramos, P., Qu, Y., Chojnowska-Monga, M., del Caño-Espinel, M., Prokop, A., and Sánchez-Soriano, N. (2016). Tau and spectraplakins promote synapse formation and maintenance through Jun kinase and neuronal trafficking. eLife 5, e14694.
Berthoumieu, O, Phuong H Nguyen, PH, del Castillo-Frias, MP, Ferre, S Tarus, B Nasica-Labouze, J Noël, S, Saurel, O, Rampon, C, Doig, AJ, Derreumaux, P, Faller, P (2015), Combined Experimental and Simulation Studies Suggest a Revised Mode of Action of the Anti‐Alzheimer Disease Drug NQ‐Trp Eur J Chemistry 21, 12657–12666
Snowden JS, Adams J, Harris J, Thompson JC, Rollinson S, Richardson A, Jones M, Neary D, Mann DM, Pickering-Brown S (2015). Distinct clinical and pathological phenotypes in frontotemporal dementia associated with MAPT, PGRN and C9orf72 mutations. Amyotroph Lateral Scler Frontotemporal Degener. 16(7-8):497-505
Continue with Facebook
