18-24 – The Emerging Role of Retrotransposons in Neurodegenerative Diseases

Transposable elements (TEs) have been associated with neurodegeneration as modulators of gene function, including changes in gene expression, alternate splicing, epigenetic modifiers and sources of cryptic exons. Through these actions, they can have pathogenic effects and have been implicated in a variety of diseases such Amyotrophic Lateral Sclerosis, Alzheimer’s and Parkinson’s disease. These TE’s are highly polymorphic within the human genome, both for presence/absence, as well as within their primary sequence. There are growing numbers of examples of mono-genic forms of disease caused by the presence of a single TE which disrupts the normal processing of a key gene. One of the most cited examples of this is a SINE-VNTR-Alu (SVA) insertion within the gene TAF1, which disrupts normal gene processing leading to the onset of X-linked dystonia parkinsonism (XDP). Our work expands the role of retrotransposons in disease, by exploring how more common elements confer risk within complex disorders. It is likely that many retrotransposons work in consort as cumulative risk factors which give rise to disease through increased risk over the course of our lifetime. We have demonstrated that an SVA element within the MAPT locus (which has strong links to multiple neurodegenerative diseases), termed SVA_67, is significantly associated with differential gene expression of several genes within the locus. We were able to show this using bioinformatic approaches, which utilised the Target ALS and Parkinson’s Progressive Markers Initiative (PPMI) datasets, as well as in vitro cell models of CRISPR modified SVA_67 knockout HEK293 cell lines. A key finding is that the regulatory properties of a specific locus are modified by the polymorphism of the TE primary sequence, in addition to its presence or absence in our genome. The former is hypothesised to reflect differential interactions of sequence specific DNA binding proteins within the TE which can impact gene function.