# Patient-derived frontotemporal lobar degeneration brain extracts induce formation and spreading of TDP-43 pathology in vivo

Article · Porta S, Xu Y, Restrepo CR, Kwong LK, Zhang B, Brown HJ, Lee EB, Trojanowski JQ, Lee VM

- Archive id: doi:10.1038/s41467-018-06548-9
- Published: 2018-10-11
- Venue: Nature communications
- DOI: https://doi.org/10.1038/s41467-018-06548-9
- PMID: 30310141
- PMCID: PMC6181940
- Citations: 212
- Source URL: https://doi.org/10.1038/s41467-018-06548-9
- PDF: https://europepmc.org/articles/PMC6181940/pdf
- Provenance: europepmc

## Abstract

The stereotypical distribution of TAR DNA-binding 43 protein (TDP-43) aggregates in frontotemporal lobar degeneration (FTLD-TDP) suggests that pathological TDP-43 spreads throughout the brain via cell-to-cell transmission and correlates with disease progression, but no in vivo experimental data support this hypothesis. We first develop a doxycycline-inducible cell line expressing GFP-tagged cytoplasmic TDP-43 protein (iGFP-NLSm) as a cell-based system to screen and identify seeding activity of human brain-derived pathological TDP-43 isolated from sporadic FTLD-TDP and familial cases with Granulin (FTLD-TDP-GRN) or C9orf72 repeat expansion mutations (FTLD-TDP-C9+). We demonstrate that intracerebral injections of biologically active pathogenic FTLD-TDP seeds into transgenic mice expressing cytoplasmic human TDP-43 (lines CamKIIa-hTDP-43 NLSm , rNLS8, and CamKIIa-208) and non-transgenic mice led to the induction of de-novo TDP-43 pathology. Moreover, TDP-43 pathology progressively spreads throughout the brain in a time-dependent manner via the neuroanatomic connectome. Our study suggests that the progression of FTLD-TDP reflects the templated cell-to-cell transneuronal spread of pathological TDP-43.

_Abstract reproduced under CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)._

Topics: [Connectomics & Brain Mapping](https://space-kitty.com/topics/connectomics)

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