Patient-derived frontotemporal lobar degeneration brain extracts induce formation and spreading of TDP-43 pathology in vivo. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: Porta, Sílvia; Xu, Yan; Restrepo, Clark; Kwong, Linda; Zhang, Bin; Brown, Hannah; Lee, Edward; Trojanowski, John; Lee, Virginia
• Is Part Of: Nature communications. Volume 9:Issue 1(2018)
• Page Start: 1
• Page End: 15
• Publication Date: 2018-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-018-06548-9
• Languages: English
• ISSNs: 2041-1723

Abstract

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 withGranulin (FTLD-TDP-GRN) orC9orf72 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-43NLSm, 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. Cell-to-cell transmission of TDP43 occurs in cell cultures and may contribute to pathological TDP43 propagation in FTLD-TDP. In this study, the authors demonstrate using mouse models that a single intracerebral injection of human brain-derived pathological TDP43 from FTLD-TDP cases initiates the process of seeding and spreading of TDP43 pathology in a spatio-temporal dependent manner in the brain.