Journal Article

DZNE-2020-05557

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Antibodies inhibit transmission and aggregation of C9orf72 poly-GA dipeptide repeat proteins.

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

2017
EMBO Press Heidelberg

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Please use a persistent id in citations: doi:10.15252/emmm.201607054

Abstract: 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.

Keyword(s): Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Amyotrophic Lateral Sclerosis: pathology (MeSH) ; Amyotrophic Lateral Sclerosis: therapy (MeSH) ; Animals (MeSH) ; Antibodies: therapeutic use (MeSH) ; Brain: metabolism (MeSH) ; Brain: pathology (MeSH) ; C9orf72 Protein: genetics (MeSH) ; Cells, Cultured (MeSH) ; HEK293 Cells (MeSH) ; Humans (MeSH) ; Immunotherapy: methods (MeSH) ; Neurons: metabolism (MeSH) ; Neurons: pathology (MeSH) ; Protein Aggregation, Pathological: genetics (MeSH) ; Protein Aggregation, Pathological: pathology (MeSH) ; Protein Aggregation, Pathological: therapy (MeSH) ; Rats (MeSH) ; Antibodies ; C9orf72 Protein ; C9orf72 protein, human

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Contributing Institute(s):

1. Adaptive Immunity in Neurodegeneration (AG Zhou)
2. Cell Biology of Neurodegeneration (AG Edbauer)
3. Monoclonal Antibodies (AG Feederle)
4. U Clinical Researchers - Magdeburg (U Clinical Researchers - Magdeburg)
5. Clinical Neurodegeneration (AG Levin)
6. Clinical Dementia Research (Rostock /Greifswald) (AG Teipel)
7. Molecular Neurodegeneration (AG Haass)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)
2. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)

Appears in the scientific report 2017

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Database coverage:
; ; ; ; BIOSIS Previews ; Clarivate Analytics Master Journal List ; DOAJ Seal ; IF >= 10 ; JCR ; SCOPUS ; Web of Science Core Collection

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