A single-cell, long-read, isoform-resolved case-control study of FTD reveals cell-type-specific and broad splicing dysregulation in human brain
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.
Authors
- Lea T. Grinberg (ORCID: https://orcid.org/0000-0002-6809-0618)
- Wen Hu (ORCID: https://orcid.org/0000-0002-0604-2119)
- Julien Jarroux (ORCID: https://orcid.org/0000-0002-7185-6960)
- Priyanka Rao‐Ruiz (ORCID: https://orcid.org/0000-0001-9504-1427)
- Alissa L. Nana (ORCID: https://orcid.org/0000-0003-3474-8044)
- Anoushka Joglekar (ORCID: https://orcid.org/0000-0002-7818-6867)
- Shaun Pollard
- Andrey D. Prjibelski (ORCID: https://orcid.org/0000-0003-2816-4608)
- Michael Snyder (ORCID: https://orcid.org/0000-0003-0784-7987)
- Salvatore Spina (ORCID: https://orcid.org/0000-0003-3570-9143)
- Johnathan Cooper‐Knock (ORCID: https://orcid.org/0000-0002-0873-8689)
- Bruce L. Miller (ORCID: https://orcid.org/0000-0002-2152-4220)
- August Benjamin Smit (ORCID: https://orcid.org/0000-0002-2286-1587)
- Harro Seelaar (ORCID: https://orcid.org/0000-0003-1989-7527)
- Roberta Giannelli (ORCID: https://orcid.org/0000-0002-0986-6500)
- Yi He (ORCID: https://orcid.org/0000-0002-6641-5618)
- Sabine Spijker (ORCID: https://orcid.org/0000-0002-6814-2019)
- Sadaf Amin (ORCID: https://orcid.org/0000-0002-3758-6485)
- Alexandru I. Tomescu (ORCID: https://orcid.org/0000-0002-5747-8350)
- Careen Foord (ORCID: https://orcid.org/0000-0003-2984-834X)
- M. Elizabeth Ross (ORCID: https://orcid.org/0000-0001-6440-8089)
- Shiaoching Gong (ORCID: https://orcid.org/0000-0002-5907-5539)
- Hagen Tilgner (ORCID: https://orcid.org/0000-0002-7058-3606)
- Justine Hsu (ORCID: https://orcid.org/0000-0003-2713-5119)
- Li Gan (ORCID: https://orcid.org/0000-0003-4600-275X)
- Claire D. Clelland (ORCID: https://orcid.org/0000-0002-9112-2278)
- Li Fan (ORCID: https://orcid.org/0000-0003-1780-6919)
- Natan Belchikov (ORCID: https://orcid.org/0000-0002-3816-7055)
- Sai Zhang (ORCID: https://orcid.org/0000-0001-5996-6086)
- William W. Seeley
Institutions
- University of Helsinki (FI)
- University of California, San Francisco (US)
- Cornell University (US)
- Erasmus MC (NL)
- MIND Research Institute (US)
- University Memory and Aging Center (US)
- Amsterdam Neuroscience (NL)
- Stanford Medicine (US)
- Cognitive Research (United States) (US)
- University of Sheffield (GB)
- Erasmus University Rotterdam (NL)
- Stanford University (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-09-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.116198
- Citations
- 2
- Primary Topic
- RNA Research and Splicing
- Type
- article
- Field-Weighted Citation Impact
- 1.61