MAPT haplotype-associated transcriptomic changes in progressive supranuclear palsy

作者：Hadley W. Ressler, Jack Humphrey, Ricardo A. Vialle, Bergan Babrowicz, Shrishtee Kandoi, Towfique Raj, Dennis W. Dickson, Nilüfer Ertekin‐Taner, John F. Crary, Kurt Farrell · 发表于：Acta Neuropathologica Communications · 年份：2024 · DOI：10.1186/s40478-024-01839-3 · 被引用次数：16 · 研究领域：Alzheimer's disease research and treatments、RNA Research and Splicing、RNA regulation and disease

Progressive supranuclear palsy (PSP) is a neurodegenerative movement and cognitive disorder characterized by abnormal accumulation of the microtubule-associated protein tau in the brain. Biochemically, inclusions in PSP are enriched for tau proteoforms with four microtubule-binding domain repeats (4R), an isoform that arises from alternative tau pre-mRNA splicing. While preferential aggregation and reduced degradation of 4R tau protein is thought to play a role in inclusion formation and toxicity, an alternative hypothesis is that altered expression of tau mRNA isoforms plays a causal role. This stems from the observation that PSP is associated with common variation in the tau gene (MAPT) at the 17q21.31 locus which contains low copy number repeats flanking a large recurrent genomic inversion. The complex genomic structural changes at the locus give rise to two dominant haplotypes, termed H1 and H2, that have the potential to markedly influence gene expression. Here, we explored haplotype-dependent differences in gene expression using a bulk RNA-seq dataset derived from human post-mortem brain tissue from PSP (n = 84) and controls (n = 77) using a rigorous computational pipeline, including alternative pre-mRNA splicing. We found 3579 differentially expressed genes in the temporal cortex and 10,011 in the cerebellum. We also found 7214 differential splicing events in the temporal cortex and 18,802 in the cerebellum. In the cerebellum, total tau mRNA levels and the proportion o...