Using C. elegans to understand seeding and spreading of tau aggregation
Lead Research Organisation:
MRC Laboratory of Molecular Biology
Department Name: Neurobiology
Abstract
Alzheimer's disease (AD) is a common and devastating neurodegenerative disorder, and there are currently no effective treatments for it. The underlying cause of AD is believed to be the "clumping" together of proteins called ABeta and tau into large structures called aggregates. These clumps, once formed, may then spread into different cells of the brain. We aim to discover how clumps of tau form and spread between cells, and how we might be able to prevent this from happening. First of all, we will find out whether other proteins that normally clump together when cells get older might cause the formation of tau aggregates that lead to disease. Next, we will genetically manipulate a microscopic worm called Caenorhabditis elegans (C. elegans) to produce tau in different cells, giving us a better way to investigate how tau clumps together and spreads between cells, as C. elegans are easy to genetically modify. We will then change the expression of different genes in C. elegans, to see whether this affects the progress of tau clumping and spreading. In particular, we will change the levels of the proteins that normally form aggregates with age, to see how this affects tau; and we will investigate a pathway called the unfolded protein response (UPR) that is also able to spread between cells, to see if this affects the spreading of tau. If we find ways to influence the formation and spreading of tau aggregates, these genes and the molecular pathways may make promising targets for the development of new drugs against AD, a hugely important goal that could ultimately improve the lives of thousands of AD sufferers and their carers.
Technical Summary
Tau aggregation is a prominent feature of many neurodegenerative diseases, including Alzheimer's disease (AD), for which the most prominent risk factor is ageing. The reasons underlying the age-associated nature of disease progression are not yet understood. Recent evidence suggests that tau aggregation can be seeded and propagates in a prion-like manner, by mechanisms that are also currently unclear. We aim to determine whether proteins that normally aggregate with age as a result of the age-dependent decline of proteostasis mechanisms can act as seeds for tau aggregation. We also aim to develop novel C. elegans models for the spreading of tau aggregation between cells, in order to gain a better understanding of the pathways and processes underlying the propagation of tau misfolding. We will then test candidate genes and pathways, including aggregative proteins identified as seeding tau aggregation, and the unfolded protein response in the ER (UPRER), for their effects on tau aggregate propagation in this model. By these means we aim to determine pathways underlying the seeding and spreading of tau aggregation, providing insights that could potentially be used for the development of novel therapeutics against tauopathies.
Planned Impact
This work will improve our understanding of tau-related dementias, and as such will benefit researchers in this and related areas. In addition, we believe that this work may uncover drug targets for treatment of these dementias. If such drugs are developed as a result of this work, this will have major benefits for people suffering from dementia and their carers.
People |
ORCID iD |
Rebecca Taylor (Principal Investigator) |
Publications
Imanikia S
(2018)
Cell Non-autonomous UPRER Signaling.
in Current topics in microbiology and immunology
Description | Centres of Excellence in Neurodegeneration (CoEN) Pathfinder II Award |
Amount | £172,988 (GBP) |
Organisation | Network of Centres of Excellence in Neurodegeneration (COEN) |
Sector | Public |
Country | United Kingdom |
Start | 05/2016 |
End | 04/2018 |
Title | Isolation of C. elegans tissues |
Description | We have developed a method to dissociate the cells of C. elegans, and sort different cell and tissue types using fluorescent labelling followed by flow cytometry. Using this technique, we have successfully isolated neuronal and intestinal cells for RNA-seq analysis. |
Type Of Material | Biological samples |
Year Produced | 2017 |
Provided To Others? | No |
Impact | We have been able to isolate neuronal and intestinal cells from genetically modified C. elegans for RNA-seq analysis. This has allowed us to explore the tissue-specific gene expression changes induced by neuronal expression of the transcription factor Xbp-1s, helping us to understand its cell autonomous and cell non-autonomous roles. We aim to publish this work, and the associated methodology, in 2018/2019. |
Description | Identifying aggregative protein seeds |
Organisation | German Centre for Neurodegenerative Diseases |
Country | Germany |
Sector | Public |
PI Contribution | We are analysing the roles of naturally aggregative proteins identified by our collaborators, in the seeding of aggregates of human disease proteins in C. elegans models |
Collaborator Contribution | Our collaborators are identifying C. elegans and mouse proteins that may act as seeds for protein aggregation |
Impact | No outputs yet. |
Start Year | 2016 |
Description | "Finding the fountain of youth: Why we age and what we can do about it " - Talk at Cambridge Science Festival |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | This was a talk aimed at the general public at the Cambridge Science Festival. Over 100 people attended. I aimed to convey a knowledge of the history and current state of knowledge in research on ageing, focusing finally on insights gained by my group using the model organism C. elegans. There was a lively discussion during the question session afterwards, and post-talk feedback was very good; 93% of those that responded to our feedback request rated the event good or very good, and the score for what they had learned was 8.5/10. |
Year(s) Of Engagement Activity | 2017 |
Description | "Worms are cleverer than you think!" - Educational outreach activity at Cambridge Science Festival |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | "Worms are cleverer than you think!" was an educational outreach activity aimed at children aged 7-11. This was held over the course of a day as part of the Cambridge Science Festival, and was designed to spark an interest in science in children through games and activities that show how worms can be used to study the senses, ageing and neurodegeneration, and how we think. The day was a success, with over 100 children participating, and with great feedback from those who completed our feedback survey. |
Year(s) Of Engagement Activity | 2017 |
URL | https://www.sciencefestival.cam.ac.uk/system/files/cambridge_science_festival_2017_0.pdf |
Description | "Worms are cleverer than you think!" at the LMB Open Day |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | We reprised our "Worms are cleverer than you think!" educational outreach activity for the LMB Open Day in June 2017. The event reached a large number of people interested in the research carried out at the LMB, and we again received good feedback on our worm-based activity. |
Year(s) Of Engagement Activity | 2017 |
URL | http://www2.mrc-lmb.cam.ac.uk/news-and-events/public-engagement/open-day/ |
Description | 2017 Big Biology Day |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Volunteered at the 2017 Big Biology Day, a one day science festival at Hill's Road College in Cambridge aimed at allowing the public to meet and better understand scientists and the work they do, where we showed our "Worms are Cleverer Than You Think!" outreach activity. |
Year(s) Of Engagement Activity | 2017 |
URL | http://www.hillsroad.ac.uk/college-life/events/2017/10/14/default-calendar/big-biology-day |
Description | Article in Oxford-based "Phenotype" magazine |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Postgraduate students |
Results and Impact | This article in Oxford-based "Phenotype" magazine was aimed at postgraduate and undergraduate students from other disciplines, to introduce them to the principles of our work on neurodegeneration. |
Year(s) Of Engagement Activity | 2017 |
URL | https://issuu.com/phenotypejournal/docs/mt17-1 |
Description | CamAST (Cambridge Academy of Science & Technology) volunteer |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Gave a talk at the local 6th form college CamAST (Cambridge Academy of Science & Technology), telling students a personal story about life in science; this will be followed by weekly science engagement activities for year 11 students. |
Year(s) Of Engagement Activity | 2018 |
Description | Helped to create an immersive experience piece: Home in The Service of Science (part of the Festival of Ideas) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | An immersive installation at the LMB was opened to the public in order to communicate science in a novel manner. It inspired much interest and opened lines of communication between scientists and lay people. |
Year(s) Of Engagement Activity | 2016 |
URL | http://www2.mrc-lmb.cam.ac.uk/homeinsci/performance/ |
Description | Hosted a high school student for one week, to work on a short project: "Comparing the characteristics of tau aggregates between different transgenic C. elegans strains" |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | We hosted a high school student for one week, August 13th-17th 2018, giving him an introduction to life in science. Along with teaching some theory, we also taught several practical techniques, and the student used those to address a short project: "Comparing the characteristics of tau aggregates between different transgenic C. elegans strains". The week ended with our student writing a report on his findings, and what he had learned, along with a career advice session. |
Year(s) Of Engagement Activity | 2018 |
Description | LMB seminar for non-science staff |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Other audiences |
Results and Impact | I gave a seminar designed for a general audience, to the non-scientific staff of the LMB. The talk aimed to help those not directly participating in research at the LMB to understand my groups work, and what we are trying to achieve in the long term. |
Year(s) Of Engagement Activity | 2016 |
Description | STEM ambassador |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Volunteering with the stem.org.uk "STEM ambassador" programme. This involves visits to schools and colleges to talk about careers in STEM fields. |
Year(s) Of Engagement Activity | 2017,2018 |
URL | https://www.stem.org.uk/stem-ambassadors |
Description | Talk at Downing college: "From Mad Cow Disease to Alzheimer's: what worms can tell us about prion biology" |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | A presentation to a general undergraduate and postgraduate audience at Downing college, titled: "From Mad Cow Disease to Alzheimer's: what worms can tell us about prion biology". |
Year(s) Of Engagement Activity | 2018 |
Description | TaylorLabLMB Twitter account |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | TaylorLabLMB is the Taylor lab Twitter account, aimed at spreading awareness of our work, our public engagement activities, other local engagement events, and related work within the fields of ageing and neurodegenerative disease, to a general as well as a scientific audience. The account has followers, and in 2017 sent out tweets, receiving significant engagement from a range of individuals and organisations. |
Year(s) Of Engagement Activity | 2016,2017,2018 |
URL | https://twitter.com/TaylorLabLMB |