Grant: Master's Award: Canada Graduate Scholarships

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affect the motor neurons of the central nervous system. This motor neuron death leads to progressive loss of muscle function resulting in death within 2-5 years of diagnosis. Endogenous retroviruses (ERVs) are viral elements that make up 8% of the human genome. These ERVs have been associated with ALS neuropathology, along with other inflammatory and neurological diseases. Endogenous Retrovirus-K (ERVK) is a viral parasite that is known to produce a functionally active enzyme integrase (IN). The Douville lab has found high levels of ERVK IN expression in ALS brain and spinal cord tissue. Along with this IN expression, there is also an increase in expression of DNA damage markers ?H2AX and the disruption of DNA repair protein BRCA1. This DNA damage can lead to a form of inflammatory programmed cell death known as necroptosis. Our research will involve the generation of human cerebral organoids with a cumate-inducible ERVK IN vector. These organoids will be treated with cumate to induce ERVK IN expression and DNA damage, inflammation, and necroptosis patterns will be assessed. We will also test known integrase inhibitors on these IN-expressing organoids to test the ability of these drugs in preventing this damage and cell death. If successful, these anti-retroviral drugs may be used in future ALS clinical trials, and provide a basis for desperately needed therapies.