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

Sílvia Porta, Yan Xu, Clark R. Restrepo, Linda K. Kwong, Bin Zhang, Hannah J. Brown, Edward B. Lee, John Q. Trojanowski and Virginia M.-Y. Lee ()
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Sílvia Porta: University of Pennsylvania
Yan Xu: University of Pennsylvania
Clark R. Restrepo: University of Pennsylvania
Linda K. Kwong: University of Pennsylvania
Bin Zhang: University of Pennsylvania
Hannah J. Brown: University of Pennsylvania
Edward B. Lee: University of Pennsylvania
John Q. Trojanowski: University of Pennsylvania
Virginia M.-Y. Lee: University of Pennsylvania

Nature Communications, 2018, vol. 9, issue 1, 1-15

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 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-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.

Date: 2018
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DOI: 10.1038/s41467-018-06548-9

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