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EMBO J. 2020 Mar 16:e102811. doi: 10.15252/embj.2019102811. [Epub ahead of print]

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

Author information

1
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
2
Graduate School of Systemic Neurosciences (GSN), Ludwig-Maximilians-University Munich, Munich, Germany.
3
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, Germany.
4
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
5
Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany.
6
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Munich, Germany.
7
Department of Biomedical Sciences of Cells and Systems, University of Groningen, Groningen, The Netherlands.
8
School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, Oldenburg, Germany.
#
Contributed equally

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.

KEYWORDS:

C9orf72 ; antibody therapy; neurodegeneration; nucleocytoplasmic transport; proteasome

PMID:
32175624
DOI:
10.15252/embj.2019102811

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