Stable Isotope Labeling Kinetics (SILK) in patients with familial forms of neurodegenerative diseases.
Lead Research Organisation:
University College London
Department Name: Institute of Neurology
Abstract
Dementia Research Institute
The project is aligned with the Accelerating Medicines Discovery and Translation priority area as it will provide a new tool to study drugs that inhibit or modify the expression of disease-related proteins in neurodegenerative diseases.
Industrial Partner:
C2N - the project will employ the stable isotope labeling kinetic (SILK) platform, developed by C2N, in which a stable, non-radioactive isotope labeled amino acid is infused into human subjects. The stable isotope incorporates into newly synthesized proteins in the brain, which will be sampled through serial collection of plasma and CSF. In the first phase, we will determine production and clearance rates of TDP-43, tau, -synuclein and novel short A species. The PhD student will focus on laboratory measurements in the project.
The project is aligned with the Accelerating Medicines Discovery and Translation priority area as it will provide a new tool to study drugs that inhibit or modify the expression of disease-related proteins in neurodegenerative diseases.
Industrial Partner:
C2N - the project will employ the stable isotope labeling kinetic (SILK) platform, developed by C2N, in which a stable, non-radioactive isotope labeled amino acid is infused into human subjects. The stable isotope incorporates into newly synthesized proteins in the brain, which will be sampled through serial collection of plasma and CSF. In the first phase, we will determine production and clearance rates of TDP-43, tau, -synuclein and novel short A species. The PhD student will focus on laboratory measurements in the project.
Publications
Paterson RW
(2019)
SILK studies - capturing the turnover of proteins linked to neurodegenerative diseases.
in Nature reviews. Neurology
| Description | ARUK Travel Grant |
| Amount | £336 (GBP) |
| Organisation | Alzheimer's Research UK |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 06/2019 |
| End | 08/2019 |
| Description | UCL-Birkbeck MRC DTP - Training and Conference grant |
| Amount | £1,142 (GBP) |
| Organisation | MRC Doctoral Training Program |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 06/2019 |
| End | 08/2019 |
| Description | Stable Isotope Labelling Kinetics and Characterisation of Proteins in Neurodegeneration |
| Organisation | Washington University in St Louis |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | For this collaboration, we are responsible for setting up a Stable Isotope Labelling Kineitcs (SILK) study location at UCL. This includes studying the kinetics of Neurofilament Light Chain (a general biomarker of neurodegeneration) in both the human central nervous system (by analysing cerebrospinal fluid) and in in vitro models (iPSC-derived neuronal cultures). We are also studying a protein called amyloid-beta in familial Alzheimer's disease iPSC-derived models. In particular, this funding is crucial for me to establish the analytical methods and techniques at UCL that will allow us to assess protein kinetics. This includes development of in vitro SILK protocols and targeted mass spectrometry assays that allow us to determine the enrichment of stable isotope tracers and the turnover of protein, which for this collaboration primarily focuses on neurofilament light chain. |
| Collaborator Contribution | We collaborate very closely with Professor Randall Bateman's group based at Washington University in St Louis. They pioneered the SILK technique and provide much guidance and advice on setting up SILK studies here at UCL. In the collaboration they are responsible for the characterisation of neurofilament light chain in cerebrospinal fluid by mass spectrometry, which includes looking in detail at whether post-translational modifications on the protein can distinguish between health and disease. As such, they also are working on method development using mass spectrometry, where discussions of results from both sides of the collaboration have been incredibly informative to the project. |
| Impact | Last year we published a review together on the SILK technique in Nature Reviews Neurology (doi: 10.1038/s41582-019-0222-0). |
| Start Year | 2018 |
| Description | Hosted two in2science students for a day while they were on a 2 week placement at UCL with Dr Amanda Heslegrave |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Other audiences |
| Results and Impact | I hosted two secondary school students who were on placement with Dr Amanda Heslegrave at UCL through the in2science programme. I showed the students around the induced pluripotent stem cell (iPSC) lab, and discussed with them what research is done in the lab and its potential impact and contribution in dementia research, as well as other research fields these models are currently used in. The students were shown stem cells, neuronal precursors, neurons, microglia, astrocytes and cerebral organiods that are grown in the lab and are being used currently being used in dementia research by Wray Lab team at UCL. We also discussed the students thoughts and hopes for the future and where they hoped their interest in science could take them. This also provided an opportunity for the students to ask questions about a wide range of topics, including university applications, selecting courses and different fields and careers in science. |
| Year(s) Of Engagement Activity | 2019 |
| URL | https://in2scienceuk.org/ |
| Description | Presentation at Genetics and Genomic Medicine Programme Junior Researcher Symposium: Translational Research in Rare Diseases |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | I was invited to present at the Genetics and Genomic Medicine Programme Junior Researcher Symposium: Translational Research in Rare Diseases. My talk focused on Stable Isotope Labelling Kinetics (SILK) in iPSC-derived cell models and patients with neurodegenerative diseases. This sparked questions from both researchers and clinicians and encouraged a discussion on how SILK could be used to study other rare and neurodegenerative disorders in both human study participants and in vitro and in vivo research models. |
| Year(s) Of Engagement Activity | 2019 |
| URL | https://www.eventbrite.co.uk/e/ggm-junior-researcher-symposium-translational-research-in-rare-diseas... |
| Description | Presentation at New Frontiers in CSF Research symposium: Neurodegeneration and CSF |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Professional Practitioners |
| Results and Impact | I gave a talk entitled Neurodegeneration and CSF at the New Frontiers in CSF Research symposium, which was held on February 13th, 2020 at UCL. The audience consisted of mainly neurosurgeons, nuerologists, clinical scientist, scientists and PhD students, and the purpose of the symposium was to establish what is currently known regarding cereborspinal fluid and its applications, and importantly what still is not known. This opened up discussions within the group, particularly regarding potential future collaborations between clinicians and researchers. |
| Year(s) Of Engagement Activity | 2020 |
| URL | https://www.ucl.ac.uk/ion/events/2020/feb/new-frontiers-csf-research-queen-square-symposium |
| Description | Public engagement activity at Southbank Centre to promote wider understanding of dementia research: Neuronal Disco |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Public/other audiences |
| Results and Impact | This was a public engagement activity as part of Created Out of Mind, and the event was led by artist Charlie Murphy and molecular neuroscientist Dr Selina Wray. The aim of this workshop was to encourage the general public to be curious and learn about the dynamic properties of the brain, and in particular neurons used in dementia research, through a fun and interactive dance workshop. This was in line with the overarching goal to help explore and promote understanding of dementia through science and creative arts. |
| Year(s) Of Engagement Activity | 2018 |
| URL | https://www.southbankcentre.co.uk/whats-on/128414-neuronal-disco-2018 |