Investigating the association of endogenous mammalian retrotransposons with motor neuron disease
Lead Research Organisation:
University of Liverpool
Department Name: Institute of Translational Medicine
Abstract
The genomic DNA an individual is born with is not a stable entity and there is a class of DNA in the genome, termed retrotransposable elements, which can jump around the genome via a copy-&-paste mechanism, termed mobilization, which causes new, potentially mutagenic insertions in genomic DNA [1]. This has been observed in several cancers [2] and more recently in the adult CNS [3]. In the latter this is a normal physiological process thought be associated with aging however its also thought that inappropriate control of retrotransposon function could be associated with CNS dysfunction, e.g. neurodegenerative conditions motor neuron disease, ataxia telangiectasia and fronto-temporal lobar degeneration [4, 5]. We will further extend the model for motor neuron disease (MND). This work will benefit from ongoing related work on MND in Liverpool and Sheffield.
Importantly the mobilization of these retrotransposons requires a human endogenous reverse transcriptase and integrase enzyme to generate the copy and its reintegration in the genome. It has been shown in vitro that existing HIV antiviral drugs that target the equivalent virus enzymes can inhibit the mobilization of the retrotransposons in a cell line model [6, 7]. This is therefore one of the few potential targets for therapeutic intervention in MND.
The PhD has two main aims:
1. We will characterize retrotransposon expression in motor neurons using in vivo models and human tissue.
2. We will determine in vitro if HIV drugs inhibit retrotransposon mobilization and in vivo decrease the severity of progression of MND in well characterized animal model systems
The techniques applied will include general molecular and cellular biology, tissue culture, immunohistochemistry and in situ hybridization. The bulk of the work will be performed in Liverpool and CNS tissue for analysis will be supplied from Sheffield. The action of drugs will be analyzed in both a well characterized cell line for retrotransposon mobilization and in vivo models of MND [8].
1 Erwin, J. A., et al. (2014) Mobile DNA elements in the generation of diversity and complexity in the brain. Nat Rev Neurosci. 15, 497-506
2 Shukla, R., et al/ (2013) Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma. Cell. 153, 101-111
3 Upton, K. R. et al., (2015) Ubiquitous L1 mosaicism in hippocampal neurons. Cell. 161, 228-239
4 Li, W., et al. (2012) Transposable elements in TDP-43-mediated neurodegenerative disorders. PLoS ONE. 7, e44099
5 Li, W., et al. (2013) Activation of transposable elements during aging and neuronal decline in Drosophila. Nature neuroscience. 16, 529-531
6 Goodier, J. L., et al (2013) Mapping the LINE1 ORF1 protein interactome reveals associated inhibitors of human retrotransposition. Nucleic Acids Res. 41, 7401-7419
7 Jones, R. B., et al. (2008) Nucleoside analogue reverse transcriptase inhibitors differentially inhibit human LINE-1 retrotransposition. PLoS ONE. 3, e1547
8 Raiz, J., et al. (2012) The non-autonomous retrotransposon SVA is trans-mobilized by the human LINE-1 protein machinery. Nucleic Acids Res. 40, 1666-1683"
Importantly the mobilization of these retrotransposons requires a human endogenous reverse transcriptase and integrase enzyme to generate the copy and its reintegration in the genome. It has been shown in vitro that existing HIV antiviral drugs that target the equivalent virus enzymes can inhibit the mobilization of the retrotransposons in a cell line model [6, 7]. This is therefore one of the few potential targets for therapeutic intervention in MND.
The PhD has two main aims:
1. We will characterize retrotransposon expression in motor neurons using in vivo models and human tissue.
2. We will determine in vitro if HIV drugs inhibit retrotransposon mobilization and in vivo decrease the severity of progression of MND in well characterized animal model systems
The techniques applied will include general molecular and cellular biology, tissue culture, immunohistochemistry and in situ hybridization. The bulk of the work will be performed in Liverpool and CNS tissue for analysis will be supplied from Sheffield. The action of drugs will be analyzed in both a well characterized cell line for retrotransposon mobilization and in vivo models of MND [8].
1 Erwin, J. A., et al. (2014) Mobile DNA elements in the generation of diversity and complexity in the brain. Nat Rev Neurosci. 15, 497-506
2 Shukla, R., et al/ (2013) Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma. Cell. 153, 101-111
3 Upton, K. R. et al., (2015) Ubiquitous L1 mosaicism in hippocampal neurons. Cell. 161, 228-239
4 Li, W., et al. (2012) Transposable elements in TDP-43-mediated neurodegenerative disorders. PLoS ONE. 7, e44099
5 Li, W., et al. (2013) Activation of transposable elements during aging and neuronal decline in Drosophila. Nature neuroscience. 16, 529-531
6 Goodier, J. L., et al (2013) Mapping the LINE1 ORF1 protein interactome reveals associated inhibitors of human retrotransposition. Nucleic Acids Res. 41, 7401-7419
7 Jones, R. B., et al. (2008) Nucleoside analogue reverse transcriptase inhibitors differentially inhibit human LINE-1 retrotransposition. PLoS ONE. 3, e1547
8 Raiz, J., et al. (2012) The non-autonomous retrotransposon SVA is trans-mobilized by the human LINE-1 protein machinery. Nucleic Acids Res. 40, 1666-1683"
People |
ORCID iD |
| John Quinn (Primary Supervisor) | |
| Jack Marshall (Student) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/N013840/1 | 01/10/2016 | 30/09/2025 | |||
| 1792010 | Studentship | MR/N013840/1 | 01/10/2016 | 30/04/2020 | Jack Marshall |
| Description | Subgroup leader within Working Group 6 of Project MinE |
| Organisation | King's College London |
| Department | Institute of Psychiatry, Psychology & Neuroscience |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Was invited by Dr Johnathan Cooper-Knock (who runs Working Group 6 of Project MinE) to run a Retrotransposons subgroup. The purpose of this group is to assess non-coding genetic variation in ALS. We aim to publish some of our work on retrotransposon genetic variation found in ALS patients. |
| Collaborator Contribution | This collaboration has led to me visit other research teams involved in this working group, particularly the bioinformatics team at Kings College London. I worked alongside Dr Alfredo Iacoangeli for three weeks and received training on how to use Linux and basic bash commands (as part of the bioinformatics analysis on the Project MinE samples we are using). We also have regular meetings over Google Hangouts to discuss data analysis with the collaborators in both Sheffield (SiTraN) and Kings College London, so we get feedback on a regular basis. |
| Impact | In the process of writing a paper on the discovery of non-coding variants found within the ALS gene NEK1. |
| Start Year | 2018 |
| Description | Subgroup leader within Working Group 6 of Project MinE |
| Organisation | University of Sheffield |
| Department | Sheffield Institute for Translational Neuroscience (SITraN) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Was invited by Dr Johnathan Cooper-Knock (who runs Working Group 6 of Project MinE) to run a Retrotransposons subgroup. The purpose of this group is to assess non-coding genetic variation in ALS. We aim to publish some of our work on retrotransposon genetic variation found in ALS patients. |
| Collaborator Contribution | This collaboration has led to me visit other research teams involved in this working group, particularly the bioinformatics team at Kings College London. I worked alongside Dr Alfredo Iacoangeli for three weeks and received training on how to use Linux and basic bash commands (as part of the bioinformatics analysis on the Project MinE samples we are using). We also have regular meetings over Google Hangouts to discuss data analysis with the collaborators in both Sheffield (SiTraN) and Kings College London, so we get feedback on a regular basis. |
| Impact | In the process of writing a paper on the discovery of non-coding variants found within the ALS gene NEK1. |
| Start Year | 2018 |