Journal Article

DZNE-2020-03131

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations.

Mori, K. ; Lammich, S. ; Mackenzie, I. R. A. ; Forné, I. ; Zilow, S. ; Kretzschmar, H. ; Edbauer, D.DZNE* ; Janssens, J. ; Kleinberger, G.DZNE* ; Cruts, M. ; Herms, J.DZNE* ; Neumann, M.DZNE* ; Van Broeckhoven, C. ; Arzberger, T. ; Haass, C. (Last author)DZNE*

2013
Springer Heidelberg

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Please use a persistent id in citations: doi:10.1007/s00401-013-1088-7

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.

Keyword(s): Adaptor Proteins, Signal Transducing: metabolism (MeSH) ; Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Amyotrophic Lateral Sclerosis: metabolism (MeSH) ; Amyotrophic Lateral Sclerosis: pathology (MeSH) ; C9orf72 Protein (MeSH) ; Chromatography, High Pressure Liquid (MeSH) ; DNA-Binding Proteins: metabolism (MeSH) ; Frontotemporal Lobar Degeneration: genetics (MeSH) ; Frontotemporal Lobar Degeneration: metabolism (MeSH) ; Frontotemporal Lobar Degeneration: pathology (MeSH) ; Gene Expression Regulation: genetics (MeSH) ; HEK293 Cells (MeSH) ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B: metabolism (MeSH) ; Hippocampus: pathology (MeSH) ; Humans (MeSH) ; Inclusion Bodies: metabolism (MeSH) ; Inclusion Bodies: pathology (MeSH) ; Mass Spectrometry (MeSH) ; Mutation: genetics (MeSH) ; Proteins: genetics (MeSH) ; RNA, Small Interfering: metabolism (MeSH) ; Repetitive Sequences, Nucleic Acid: physiology (MeSH) ; Sequestosome-1 Protein (MeSH) ; Transfection (MeSH) ; Adaptor Proteins, Signal Transducing ; C9orf72 Protein ; C9orf72 protein, human ; DNA-Binding Proteins ; HNRNPA3 protein, human ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B ; Proteins ; RNA, Small Interfering ; SQSTM1 protein, human ; Sequestosome-1 Protein

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Contributing Institute(s):

1. Cell Biology of Neurodegeneration (AG Edbauer)
2. Translational Brain Research (AG Herms)
3. Molecular Neuropathology of Neurodegenerative Diseases (AG Neumann)

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 2013

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 15 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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