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01.03.2013 | Original Paper

hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations

verfasst von: Kohji Mori, Sven Lammich, Ian R. A. Mackenzie, Ignasi Forné, Sonja Zilow, Hans Kretzschmar, Dieter Edbauer, Jonathan Janssens, Gernot Kleinberger, Marc Cruts, Jochen Herms, Manuela Neumann, Christine Van Broeckhoven, Thomas Arzberger, Christian Haass

Erschienen in: Acta Neuropathologica | Ausgabe 3/2013

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Abstract

Genetic analysis revealed the hexanucleotide repeat expansion GGGGCC within the regulatory region of the gene C9orf72 as the most common cause of familial amyotrophic lateral sclerosis and the second most common cause of frontotemporal lobar degeneration. Since repeat expansions might cause RNA toxicity via sequestration of RNA-binding proteins, we searched for proteins capable of binding to GGGGCC repeats. In vitro-transcribed biotinylated RNA containing hexanucleotide GGGGCC or, as control, AAAACC repeats were incubated with nuclear protein extracts. Using stringent filtering protocols 20 RNA-binding proteins with a variety of different functions in RNA metabolism, translation and transport were identified. A subset of these proteins was further investigated by immunohistochemistry in human autopsy brains. This revealed that hnRNP A3 formed neuronal cytoplasmic and intranuclear inclusions in the hippocampus of patients with C9orf72 repeat extensions. Confocal microcopy showed that these inclusions belong to the group of the so far enigmatic p62-positive/TDP-43 negative inclusions characteristically seen in autopsy cases of diseased C9orf72 repeat expansion carriers. Thus, we have identified one protein component of these pathognomonic inclusions.

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Titel: hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations
verfasst von: Kohji Mori
Sven Lammich
Ian R. A. Mackenzie
Ignasi Forné
Sonja Zilow
Hans Kretzschmar
Dieter Edbauer
Jonathan Janssens
Gernot Kleinberger
Marc Cruts
Jochen Herms
Manuela Neumann
Christine Van Broeckhoven
Thomas Arzberger
Christian Haass
Publikationsdatum: 01.03.2013
Verlag: Springer-Verlag
Erschienen in: Acta Neuropathologica / Ausgabe 3/2013
Print ISSN: 0001-6322
Elektronische ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-013-1088-7

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