TY  - JOUR
AU  - Mori, Kohji
AU  - Lammich, Sven
AU  - Mackenzie, Ian R A
AU  - Forné, Ignasi
AU  - Zilow, Sonja
AU  - Kretzschmar, Hans
AU  - Edbauer, Dieter
AU  - Janssens, Jonathan
AU  - Kleinberger, Gernot
AU  - Cruts, Marc
AU  - Herms, Jochen
AU  - Neumann, Manuela
AU  - Van Broeckhoven, Christine
AU  - Arzberger, Thomas
AU  - Haass, Christian
TI  - hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations.
JO  - Acta neuropathologica
VL  - 125
IS  - 3
SN  - 0001-6322
CY  - Heidelberg
PB  - Springer
M1  - DZNE-2020-03131
SP  - 413-423
PY  - 2013
AB  - 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.
KW  - Adaptor Proteins, Signal Transducing: metabolism
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Amyotrophic Lateral Sclerosis: pathology
KW  - C9orf72 Protein
KW  - Chromatography, High Pressure Liquid
KW  - DNA-Binding Proteins: metabolism
KW  - Frontotemporal Lobar Degeneration: genetics
KW  - Frontotemporal Lobar Degeneration: metabolism
KW  - Frontotemporal Lobar Degeneration: pathology
KW  - Gene Expression Regulation: genetics
KW  - HEK293 Cells
KW  - Heterogeneous-Nuclear Ribonucleoprotein Group A-B: metabolism
KW  - Hippocampus: pathology
KW  - Humans
KW  - Inclusion Bodies: metabolism
KW  - Inclusion Bodies: pathology
KW  - Mass Spectrometry
KW  - Mutation: genetics
KW  - Proteins: genetics
KW  - RNA, Small Interfering: metabolism
KW  - Repetitive Sequences, Nucleic Acid: physiology
KW  - Sequestosome-1 Protein
KW  - Transfection
KW  - Adaptor Proteins, Signal Transducing (NLM Chemicals)
KW  - C9orf72 Protein (NLM Chemicals)
KW  - C9orf72 protein, human (NLM Chemicals)
KW  - DNA-Binding Proteins (NLM Chemicals)
KW  - HNRNPA3 protein, human (NLM Chemicals)
KW  - Heterogeneous-Nuclear Ribonucleoprotein Group A-B (NLM Chemicals)
KW  - Proteins (NLM Chemicals)
KW  - RNA, Small Interfering (NLM Chemicals)
KW  - SQSTM1 protein, human (NLM Chemicals)
KW  - Sequestosome-1 Protein (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:23381195
DO  - DOI:10.1007/s00401-013-1088-7
UR  - https://pub.dzne.de/record/136809
ER  -