DNA damage driven motor disturbance in ALS: An ERVK integrase transgenic mouse model

Within our genome (the complete set of DNA present in a person) are pieces of viral DNA passed along from our ancestors. These human endogenous retroviruses (HERVs) have been termed “fossil viruses” as they are the footprints of previous viral infections our ancestors experienced and have passed down through generations. It is estimated that HERVs make up from one to eight per cent of the human genome.

For the most part, HERVs are thought to be relatively innocuous, lying dormant within our cells. However, it is hypothesized that some of these HERVs have the potential to produce viral products and therefore can become active. This has led researchers to propose a role for HERVs in certain autoimmune diseases, cancers, and neurological disorders such as multiple sclerosis (MS) and ALS.

Dr. Douville has previously shown that expression of a specific HERV protein, called ERVK, may promote inflammation and motor neuron degeneration in a subset of ALS cases. However, the exact mechanism through which this occurs remains unknown.

With this grant, Dr. Douville and team will develop and validate a mouse model representative of ERVK-driven neurodegeneration. This new model will allow researchers to test on a cellular level how expression of ERVK may influence a variety of pathological mechanisms, including DNA damage, neuroinflammation, TDP-43 dysfunction and neuronal loss. The mice will also be monitored to look for changes in motor function over time.

Establishing this mouse model could lay the foundation for future drug screening studies aimed at identifying promising new antiviral drugs to test in clinical trials. There are already multiple ongoing clinical trials evaluating the effects of antiviral drugs in ALS, however, these studies are often based on Human Immunodeficiency Virus (HIV) treatment strategies. Ultimately, the team aims to use this mouse model to develop a more targeted approach specific to ALS.