It's JustiFlied: The Endogenous Retrovirus K Integrase Induces Motor Disturbances in Transgenic Drosophila

Abstract

Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative disease characterized by the loss of cortical and spinal motor neurons. Endogenous retrovirus K (ERVK) is a genomic viral symbiont that has been associated with motor neuron loss in ALS. The ERVK integrase (IN) is an enzyme with a role in driving neuropathology and motor deficit. The primary role of the viral IN enzyme is to insert viral DNA into the host cell genome. Accumulating evidence also points to ERVK IN activity causing DNA damage and genomic instability in the host. In Drosophila, retroelement activity contributes to deregulation of the ALS risk gene TARDBP (TDP-43, TBPH in Drosophila) via DNA damage-mediated cell toxicity. This suggests a dynamic interaction between TDP-43 biology, DNA damage and retroelements. I have determined that motor disability in ERVK IN expressing Drosophila correlates with neuropathological evidence of DNA damage, inflammation, and TDP-43 aggregation. Viability and behavioral assays and the Trikinetics DAM5H monitor were used to assess motor impairment in ERVK IN expressing flies. Two FDA approved HIV integrase inhibitors were administered to determine if the progression of motor impairments could be limited. Western blot analysis was used to monitor changes in ERVK IN, ãH2AV (DNA damage marker), TDP-43, PARP1 and other related proteins over time. Pathological molecular markers were correlated with behavioural assays for motor function, to identify potential biomarkers. Establishment of this model allowed me to assess the association between ERVK IN-driven motor impairment and neuropathological outcomes. Determining the effect of integrase inhibitors in ERVK IN expressing Drosophila is a crucial step towards evaluating antivirals as a novel therapeutic strategy for the reversal of motor neuron damage and motor deficit in ALS.