Dr. Renée Douville
RetroFIND Laboratory, Division of Neurodegenerative Disorders
Department of Biology, University of Winnipeg
Department of Pharmacology and Therapeutics, University of Manitoba
Endogenous retroviruses (ERVs) are genomic fossils from retroviral infections of our human ancestors and comprise over 8% of our DNA. We share a long-standing symbiosis with these viruses that inhabit our genome. Current research indicates that not all ERVs remain silent passengers within our DNA, as their reactivation is associated with several cancers, inflammatory diseases and neurological disorders. It is crucial to consider ERV expression as a potential driving force in disease pathology.
We propose a unique perspective regarding the origin of viral pathology in ALS – it stems from select viruses within our DNA. Human endogenous retrovirus-K (ERVK / HERV-K) is a genomic viral symbiont that contributes towards ALS neuropathology. We are exploring how ERVK drives motor neuron disease and inflammation through the following projects in our laboratory:
1) The Douville lab has recently discovered a new ERVK protein called conotoxin-like protein (CTXLP). We are investigating how this novel viral protein contributes to ALS neuropathology by modulating inflammatory signalling and calcium channels in neurons.
2) We have predicted and shown that the ERVK integrase enzyme (a key viral protein for virus replication) causes DNA damage. This viral protein further modulates the DNA damage response and innate immune signalling cascades. We are investigating if integrase inhibitors could be used to treat ERVK integrase mediated motor disturbances in a fruit fly model with ERVK integrase-driven motor deficits.
3) We are screening new drugs to inhibit the ERVK protease enzyme. The ERVK protease is required for viral replication and to produce mature viral proteins. Thus, blocking its activity is an important therapeutic strategy to fight ERVK.
Why is this work important?
With growing evidence of how human endogenous retrovirus-K (ERVK / HERV-K) proteins deregulate cellular processes and drive pathologic motor neuron death, our research substantially shifts current paradigms on neurodegeneration in ALS. The molecular changes induced by ERVK have important implications for defining the pathophysiology of virus-mediated motor neuron loss in ALS and warrant further investigation. The broad long-term objective of this research direction is to lay the biomedical foundation for the use of anti-retroviral therapeutics in ALS, and other ERVK-associated conditions. Our research translated into innovative treatments will give hope to individuals in clear and urgent need of effective therapeutics for ALS.
What techniques and equipment are used in this laboratory?
We are a basic science laboratory with a focus on molecular biology, confocal imaging, and drug screening in both human and Drosophila (fruit fly) model systems.
About Dr. Renée Douville
Dr. Renée N Douville, Ph.D. is a Professor in the Department of Biology at the University of Winnipeg (since 2011) and a Principal Investigator in the Division of Neurodegenerative Disorders at the St. Boniface Hospital Research Centre (since 2021). She is best known for her expertise on human endogenous retroviruses and their potential roles in neurological disease. She obtained her Ph.D. in Immunology from the University of Manitoba in 2007. Her first postdoctoral fellowship was at Johns Hopkins University in Neurology with Dr. Avindra Nath’s team, where she published a seminal report on endogenous retrovirus-K (ERVK) in Amyotrophic Lateral Sclerosis (ALS). During that time, she also completed the Leadership and Management in the Life Sciences program at the Johns Hopkins University Carey Business School. She then went on to work as a postdoctoral fellow with Dr. John Hiscott and Dr. Rongtuan Lin at the Lady Davis Institute at McGill University. Over the last few years, her work has been largely focused on the discovery of a new viral protein in ERVK called conotoxin-like protein (CTXLP) found to be strongly expressed in ALS. Recently, the Douville lab has also shown the potential benefit of therapeutically targeting the ERVK integrase enzyme as a strategy to treat motor neuron disease. It is our continued mission to investigate whether antiviral drugs targeting ERVK could be used to treat neurodegenerative diseases like ALS, and other ERVK-associated conditions.
For more information, please contact:
Renée N. Douville, PhD
Division of Neurodegenerative Disorders
St. Boniface Hospital Albrechtsen Research Centre
R4050, 351 Taché Ave
Winnipeg, Manitoba, Canada R2H 2A6
Department of Biology, University of Winnipeg
Office: (204) 235-3942
Lab: (204) 235-3946
How do endogenous retroviruses contribute to neurodegenerative disease?
Neurotrophic retroviruses like HIV and HTLV cause clinically silent central nervous system lesions long before the onset of diagnosable symptoms. Can the retroviruses within our DNA also cause neurological disease? Since my ascertainment of active loci of human endogenous retrovirus-K (ERVK / HERV-K) in cortical neurons of patients with Amyotrophic Lateral Sclerosis (ALS), my laboratory has published numerous articles on the biology and pathogenesis of ERVK. Our goal is to understand how ERVK alters cellular function at the molecular level and contributes to neurodegeneration. We study how each ERVK viral protein interacts with the cellular machinery, with a focus on how this can impact the innate immune response against the virus. This information can then be used to develop antiviral strategies to halt the pathogenic aspects of ERVK activity in brain cells. It is our continued mission to investigate whether antiviral drugs targeting ERVK could be used to treat neurodegenerative diseases like ALS, and other ERVK-associated conditions.
ERVK transgenic Drosophila exhibit severe motor deficits
We have developed ERVK transgenic Drosophila (fruit fly) to model motor deficits in ALS. Crosses using pan-neuronal and motor neuron GAL4-driver flies with UAS-CTXLP transgenic targets results in progeny exhibiting deficits in pupae eclosion and adult flies with motor disturbances. Sex-specific differences are also apparent, allowing us to investigate how ERVK driven pathology and treatments differentially impact both sexes. We use a combination of readouts, including walking, climbing and rest, to evaluate how ERVK proteins change behaviour in the flies, as well as correlating these results with molecular markers and imaging assays. We are also screening panels of antiviral drugs to see if they can restore motor function and reverse neuropathology in ERVK transgenic flies.
A unique view of viruses within the brain
Within the human brain, there are over 100 billion interconnected neurons, forming complex neuronal circuits – it is the brain’s control system that lets us walk, talk, breathe, and think. Damage to this neuronal network is a common occurrence in neurological disease. How can we identify the molecular and cellular changes in brain cells that are associated with disease progression? The instrument that has revolutionized cellular and neural network imaging is the confocal microscope. This technology can be used to image fluorescently labelled cells deep within an intact piece of brain tissue – generating a three-dimensional (3D) reconstruction of the neural network. We are using confocal microscopy to image ERVK protein expression in the human brain and spinal cord specimens, as well as within our ERVK transgenic Drosophila models to investigate how this virus alters brain cells and neural networking.
*Douville Lab trainees
Ilena Benoit*, Signy Brownell* and Renée N. Douville (2021) Predicted Cellular Interactors of the Endogenous Retrovirus-K Integrase Enzyme. Microorganisms. 14;9(7):1509. PMID: 34361946
Domenico Di Curzio*, Mamneet Gurm*, Matthew Turnbull*, Marie-Josée Nadeau*, Breanna Meek*, Julia D. Rempel, Samuel Fineblit*, Michael Jonasson*, Sherry Hebert, Jennifer Ferguson-Parry and Renée N. Douville. (2020) Pro-inflammatory signaling upregulates a neurotoxic conotoxin-like protein encrypted within human endogenous retrovirus-K. Invited article to Special Issue on NF-κB in Inflammation and Immunity. Cells, 9(7):1584. PMID: 32629888
Cody Rex*, Marie-Josée Nadeau*, Kerri Schellenberg# and Renée N. Douville#. (2019). Expression of Human Endogenous Retrovirus-K in Spinal and Bulbar Muscular Atrophy. #Co-last authors. Invited article for collection Modulation of Central Nervous System Function by Mobile Genetic Elements in Health and Disease, in Frontiers in Neurology – section Neurological infections. Front Neurology. 10: 968. PMID: 31551920
Matthew Garrett Turnbull*, Renée Nicole Douville. (2018). Related Endogenous Retrovirus-K Elements Harbour Distinct Protease Active Site Motifs. Frontiers in Microbiology. 9 (1577). PMID: 30072963
Douville RN and Nath A (2017). Human Endogenous Retrovirus-K and TDP-43 Expression Bridges ALS and HIV Neuropathology. Front Microbiol. 8:1986. PMID: 29075249
Bray S*, Turnbull M*, Hebert S, Douville RN. (2016) Insight into the ERVK integrase – propensity for DNA damage? Frontiers in Microbiology, 1;7:1941. PMID: 27990140
Manghera, M.*, Ferguson-Parry J, Lin R, Douville R. (2016) NF-kappaB and IRF1 Induce Endogenous Retrovirus K Expression via Interferon-Stimulated Response Elements in Its 5′ Long Terminal Repeat. J Virol 90, 9338-9349. PMID: 27512062
Manghera M*, Ferguson-Parry J, Douville R. (2016). TDP-43 Regulates Human Endogenous Retrovirus-K Viral Protein Accumulation. Neurobiology of Disease. S0969-9961(16)30156-5. PMID: 27370226
Mamneet Manghera* and Renée N. Douville. Endogenous Retrovirus-K Promoter: A Landing Strip for Inflammatory Transcription Factors? Retrovirology, 2013 Feb 9;10(1):16. PMID: 23394165
Renée Douville, Jiankai Liu, Jeffrey Rothstein, Avindra Nath. Identification of Active Loci of Human Endogenous Retrovirus in Neurons of Patients with Amyotrophic Lateral Sclerosis. Annals of Neurology. 2011. Jan 28, 69(1), p 141-151. PMID: 21280084
All publications may be viewed at https://pubmed.ncbi.nlm.nih.gov/?sort=date&term=Douville%20RN&cauthor_id=34361946
Chancellor’s Research Chair in Neuroprogressive Disease, University of Winnipeg (2016-2019)
Postdoctoral Fellowship, McGill Neuroinflammation CIHR Strategic Training Program (2011)
Scholarship, Carey Business School, Johns Hopkins University (2009)
Postdoctoral Fellowship, Multiple Sclerosis Society of Canada (2009)
Doctoral Research Award (IG/IPPH), Canadian Institutes of Health Research (CIHR) (2005)
2020 – Human Endogenous Retrovirus-K (HERV-K / ERVK) Protease ($0, In-kind services)
Atomwise AIMS award (A19-676)
2016-2023 – RETROEXPLORER: An Interactive Database of Endogenous Retroviruses in the Human Genome ($176,000)
Natural Sciences and Engineering Research Council of Canada (NSERC), Discovery grant
2018-2022 – Integrase inhibitors as a therapeutic modality for ALS ($300,000 USD)
ALS Association (USA), Independent Investigator Award
Co-investigators: Dr. Alberto Civetta (University of Winnipeg), Dr. Kerri Schellenberg (University of Saskatchewan), Dr. Veronique Belzil (Mayo Clinic Florida)
2019-2021 – Training the Next Generation of Female Neuroscientists in Gut Health ($6,500)
University of Winnipeg – Equity, Diversity and Inclusion (EDI) Research Award
Role: Co-investigator (PI: Dr. Danielle Defries)
Selection of past funding
2019-2020 – Expression of endogenous retrovirus-K viral proteins in immune cells from patients with ALS ($20,000 AUD), Flinders Health and Medical Research Institute 2019 Research Collaboration Program
Principal Investigator: Dr. Mary-Louise Rogers; Co-investigator: Dr. Renée Douville
2018 – Oh no NOGO!: Expanding on the discovery of ERVK CTXLP+ oligodendrocyte precursors in ALS ($8,000), Dr. Beni M. Sahai Fund for Cell and Molecular Biology for Advancement in Medical Research
Principal Applicant: Dr. Domenico Di Curzio; Co-investigator: Dr. Renée Douville
2016 – Is Endogenous Retrovirus-K a Therapeutic Target for Spinal and Bulbar Muscular Atrophy? ($3,500), Rare Disease Foundation
2014 – Identification of a Potentially Neurotoxic Viral Protein from Endogenous Retrovirus-K in Neuropsychiatric and Neurodegenerative Disease. ($4,690), Dr. Beni Sahai Fund for Cellular & Molecular Biology for Advancement in Medical Research Award
2014 – 2016 – It Cuts Both Ways: Innate Immune Responses that Drive and Limit Human Endogenous Retrovirus Expression ($126,773), Manitoba Health Research Council (MHRC) Operating grant
2013-2016 – Molecular Neuroimmunology of Human Retrovirus Infections ($98,900), Manitoba Health Research Council (MHRC) Establishment grant
2013 – Identification of a Potentially Neurotoxic Viral Protein from Endogenous Retrovirus-K in the Central Nervous System of Patients with ALS ($3,500), Rare Disease Foundation
2013-2017 – Confocal Imaging the Reactivation of Endogenous Retroviruses in Neurological Disease. ($403,392), Canada Foundation for Innovation (CFI)-Leader’s Opportunity Fund
2013 – Transcriptional Regulation of Human Endogenous Retrovirus-K in Neurodegenerative Disease. ($20,000), Manitoba Medical Services Foundation (MMSF) grant
2012 – Involvement of TDP-43 Dysregulation in Eliciting Human Endogenous Retrovirus Activity in ALS. ($40,000), ALS Association (ALSA) grant