{"id":"doi:10.1038/s41467-018-06548-9","kind":"article","title":"Patient-derived frontotemporal lobar degeneration brain extracts induce formation and spreading of TDP-43 pathology in vivo","authors":["Porta S","Xu Y","Restrepo CR","Kwong LK","Zhang B","Brown HJ","Lee EB","Trojanowski JQ","Lee VM"],"author_count":9,"year":2018,"published":"2018-10-11","venue":"Nature communications","cited_by":212,"doi":"10.1038/s41467-018-06548-9","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41467-018-06548-9","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41467-018-06548-9","updated":null,"pmid":"30310141","pmcid":"PMC6181940","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC6181940/pdf","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_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Patient-derived frontotemporal lobar degeneration brain extracts induce formation and spreading of TDP-43 pathology in vivo\" by Porta S, Xu Y, Restrepo CR et al., https://doi.org/10.1038/s41467-018-06548-9, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"connectomics","name":"Connectomics & Brain Mapping","domain_slug":"neuroscience"}],"cited_in_dossiers":[]}