UC San Diego

Alternative splicing of the gene MAPT produces several isoforms of tau protein; the overexpression of these isoforms is characteristic of tauopathies, which are untreatable neurodegenerative diseases. Though non-canonical functions of tau have begun to draw interest, tau isoforms’ role in these phenomena has not been examined and may reveal new details of tau-driven pathology. In particular, tau has been shown to promote activation of transposable elements, which are highly regulated nucleotide sequences that replicate throughout the genome and are thought to promote immunologic responses and cellular stress. In this study, we utilized differentiated SH-SY5Y cells infected with lentiviral constructs of tau isoforms and treated with beta-amyloid oligomers, along with publicly available RNA-sequencing data from human samples, to address tau isoforms’ roles in promoting cell damage and dysregulation of genes and transposable elements at a locus-specific level. Our analyses reveal that overexpression of different tau isoforms and their interactions with beta-amyloid in SH-SY5Y cells result in isoform-specific changes in the transcriptome, with tau isoforms showing locus-specific transposable element dysregulation patterns that parallel those seen in patients with Alzheimer’s disease and progressive supranuclear palsy. We also demonstrated differences in rates of cell death in SH-SY5Y cells infected with lentiviruses of different tau isoforms Transposable element expression at the locus-level showed increased dysregulation of L1 and Alu sites, which are thought to be drivers of pathology in other neurological diseases. These results demonstrate the importance of examining tau isoforms’ roles in neurodegeneration and bolster support for further examining transposable element dysregulation in tauopathies.