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  Cell-to-cell transmission of C9orf72 poly-(Gly-Ala) triggers key features of ALS/FTD

Khosravi, B., LaClair, K. D., Riemenschneider, H., Zhou, Q., Frottin, F., Mareljic, N., et al. (2020). Cell-to-cell transmission of C9orf72 poly-(Gly-Ala) triggers key features of ALS/FTD. EMBO JOURNAL, 39(8): e102811. doi:10.15252/embj.2019102811.

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 Creators:
Khosravi, Bahram1, Author
LaClair, Kathrine D.1, Author
Riemenschneider, Henrick1, Author
Zhou, Qihui1, Author
Frottin, Frederic2, Author              
Mareljic, Nikola1, Author
Czuppa, Mareike1, Author
Farny, Daniel1, Author
Hartmann, Hannelore1, Author
Michaelsen, Meike1, Author
Arzberger, Thomas1, Author
Hartl, F. Ulrich2, Author              
Hipp, Mark S.2, Author              
Edbauer, Dieter1, Author
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1external, ou_persistent22              
2Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565152              

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Free keywords: DIPEPTIDE-REPEAT PROTEINS; NUCLEOCYTOPLASMIC TRANSPORT; HEXANUCLEOTIDE REPEAT; FLUORESCENT PROTEINS; TDP-43 PATHOLOGY; PHASE-SEPARATION; MOTOR DEFICITS; GGGGCC REPEAT; RAN PROTEINS; MOUSE MODELantibody therapy; C9orf72; neurodegeneration; nucleocytoplasmic transport; proteasome;
 Abstract: The C9orf72 repeat expansion causes amyotrophic lateral sclerosis and frontotemporal dementia, but the poor correlation between C9orf72-specific pathology and TDP-43 pathology linked to neurodegeneration hinders targeted therapeutic development. Here, we addressed the role of the aggregating dipeptide repeat proteins resulting from unconventional translation of the repeat in all reading frames. Poly-GA promoted cytoplasmic mislocalization and aggregation of TDP-43 non-cell-autonomously, and anti-GA antibodies ameliorated TDP-43 mislocalization in both donor and receiver cells. Cell-to-cell transmission of poly-GA inhibited proteasome function in neighboring cells. Importantly, proteasome inhibition led to the accumulation of TDP-43 ubiquitinated within the nuclear localization signal (NLS) at lysine 95. Mutagenesis of this ubiquitination site completely blocked poly-GA-dependent mislocalization of TDP-43. Boosting proteasome function with rolipram reduced both poly-GA and TDP-43 aggregation. Our data from cell lines, primary neurons, transgenic mice, and patient tissue suggest that poly-GA promotes TDP-43 aggregation by inhibiting the proteasome cell-autonomously and non-cell-autonomously, which can be prevented by inhibiting poly-GA transmission with antibodies or boosting proteasome activity with rolipram.

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Language(s): eng - English
 Dates: 2020
 Publication Status: Published online
 Pages: 19
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000526932700008
DOI: 10.15252/embj.2019102811
 Degree: -

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Title: EMBO JOURNAL
Source Genre: Journal
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Publ. Info: 111 RIVER ST, HOBOKEN 07030-5774, NJ USA : WILEY
Pages: - Volume / Issue: 39 (8) Sequence Number: e102811 Start / End Page: - Identifier: ISSN: 0261-4189