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Zhou, Q.* ; Lehmer, C.* ; Michaelsen, M.* ; Mori, K.* ; Alterauge, D.* ; Baumjohann, D.* ; Schludi, M.H.* ; Greiling, J.* ; Farny, D.* ; Flatley, A. ; Feederle, R. ; May, S.* ; Schreiber, F.* ; Arzberger, T.* ; Kuhm, C.* ; Klopstock, T.* ; Hermann, A.* ; Haass, C.* ; Edbauer, D.*

Antibodies inhibit transmission and aggregation of C9orf72 poly-GA dipeptide repeat proteins.

EMBO Mol. Med. 9, 687-702 (2017)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Cell-to-cell transmission of protein aggregates is an emerging theme in neurodegenerative disease. Here, we analyze the dipeptide repeat (DPR) proteins that form neuronal inclusions in patients with hexanucleotide repeat expansion C9orf72, the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Sense and antisense transcripts of the (G4C2)n repeat are translated by repeat-associated non-ATG (RAN) translation in all reading frames into five aggregating DPR proteins. We show that the hydrophobic DPR proteins poly-GA, poly-GP, and poly-PA are transmitted between cells using co-culture assays and cell extracts. Moreover, uptake or expression of poly-GA induces nuclear RNA foci in (G4C2)80-expressing cells and patient fibroblasts, suggesting an unexpected positive feedback loop. Exposure to recombinant poly-GA and cerebellar extracts of C9orf72 patients increases repeat RNA levels and seeds aggregation of all DPR proteins in receiver cells expressing (G4C2)80 Treatment with anti-GA antibodies inhibits intracellular poly-GA aggregation and blocks the seeding activity of C9orf72 brain extracts. Poly-GA-directed immunotherapy may thus reduce DPR aggregation and disease progression in C9orf72 ALS/FTD.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords C9orf72 ; Ran Translation ; Amyotrophic Lateral Sclerosis ; Immunotherapy ; Seeding; To-cell Transmission; Anti-tau Antibodies; Hexanucleotide Repeat; Frontotemporal Dementia; Passive-immunization; Alzheimers-disease; Mouse Model; Pathology; Expansions; Toxicity
ISSN (print) / ISBN 1757-4676
e-ISSN 1757-4684
Journal EMBO Molecular Medicine
Quellenangaben Volume: 9, Issue: 5, Pages: 687-702 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Chichester
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) CF Monoclonal Antibodies (CF-MAB)