A single-cell, long-read, isoform-resolved case-control study of FTD reveals cell-type-specific and broad splicing dysregulation in human brain.

Cell reports 2025

Belchikov N, Hu W, Fan L, Joglekar A, He Y, Foord C, Jarroux J, Hsu J, Pollard S, Amin S, Prjibelski AD, Gong S, Zhang S, Giannelli R, Seelaar H, Tomescu AI, Ross ME, Li AN, Grinberg LT, Spina S, Miller BL, Cooper-Knock J, Snyder MP, Seeley WW, Rao-Ruiz P, Spijker S, Smit AB, Clelland CD, Gan L, Tilgner HU

Abstract

Progranulin-deficient frontotemporal dementia (GRN-FTD) is a major cause of familial FTD with TAR DNA-binding protein 43 (TDP-43) pathology, which is linked to exon dysregulation. However, little is known about this dysregulation in glial and neuronal cells. Here, using splice-junction-covering enrichment probes, we introduce single-nuclei long-read RNA sequencing 2 (SnISOr-Seq2), targeting 3,630 high-interest genes without loss of precision, and complete the first single-cell, long-read-resolved case-control study for neurodegeneration. Exons affected by FTD-associated skipping are shorter than those whose inclusion is increased. Up to 30% of cell-(sub)type-specific splicing dysregulation is masked by other cell types or cortical layers. Surprisingly, strong splicing dysregulation events can occur in select but not all cell types. In some cases, a cell type switches in FTD to the splicing pattern of a different cell type. In addition, in separate GRN-FTD samples, the more FTD-prone frontal cortex exhibits more FTD-associated splicing patterns than the occipital cortex. Our methodologies are widely applicable to brain and other diseases.

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