A025 Transposable elements in Huntington’s disease: do they have a role?

<h3>Background</h3> Huntington’s Disease (HD) is a genetic neurodegenerative disease for which there is currently no disease-modifying treatment. Among several underlying pathogenic mechanisms proposed to be involved in HD pathogenesis is inflammation; there is now accumulating evidence that the immune system may play an integral role in disease pathology and progression. Transposable elements (TE), aka ‘jumping genes’, are being investigated in neurodegenerative diseases as potential drivers of neuroinflammation and disease pathology. TE are thought to drive disease through two main mechanisms; (i) neuroinflammation, as expressed TE gene products trigger an inflammatory response and (ii) through promoting DNA modifications, hastening neuronal cell loss potentially contributing to somatic instability. Previous work by our team has found brain regional specific TE expression correlating with neuroinflammation and local interferon response in Parkinson’s disease post mortem tissue. There has been little investigation into TEs in HD, with no HD literature exploring the role of TEs, inflammation and somatic instabilty. <h3>Aims</h3> The overarching objective is to ascertain whether the expression of TE’s such as LINE-1s and ERVs, occurs in the brain of patients dying with Huntington’s disease (HD) and by so doing contributes to CNS neuroinflammation and CAG somatic instability. <h3>Methods</h3> Fresh frozen human brain tissue from three brain regions (prefrontal cortex, striatum and cerebellum) will be investigated across 6 HD and 6 control cases. Single nuclear RNA sequencing (snRNAseq), NanoString neuroinflammation gene panels, and long read sequencing will be used to determine TE expression, inflammation and somatic instability respectively.