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Acta Neuropathol. 2019 Oct 23. doi: 10.1007/s00401-019-02082-0. [Epub ahead of print]

Poly-glycine-alanine exacerbates C9orf72 repeat expansion-mediated DNA damage via sequestration of phosphorylated ATM and loss of nuclear hnRNPA3.

Author information

1
German Center for Neurodegenerative Diseases (DZNE) Munich, 81377, Munich, Germany.
2
Department of Psychiatry, Osaka University Graduate School of Medicine, Yamadaoka 2-2 D3, Suita, 565-0871, Osaka, Japan.
3
Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, 81377, Munich, Germany.
4
Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität München, 81377, Munich, Germany.
5
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians Universität München, 80336, Munich, Germany.
6
Department of Neurology, Technische Universität Dresden, 01307, Dresden, Germany.
7
Translational Neurodegeneration Section "Albrecht-Kossel", Department of Neurology and Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, University of Rostock, 18147, Rostock, Germany.
8
German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, 18147, Rostock, Germany.
9
Institute for Pathology, Kanstonsspital St. Gallen, Rorschacher Strasse 95, 9007, St. Gallen, Switzerland.
10
Muskelzentrum/ALS Clinic, Kantonsspital St. Gallen, Rorschacher Strasse 95, 9007, St. Gallen, Switzerland.
11
Munich Cluster for System Neurology (SyNergy), 81377, Munich, Germany.
12
German Center for Neurodegenerative Diseases (DZNE) Munich, 81377, Munich, Germany. christian.haass@mail03.med.uni-muenchen.de.
13
Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, 81377, Munich, Germany. christian.haass@mail03.med.uni-muenchen.de.
14
Munich Cluster for System Neurology (SyNergy), 81377, Munich, Germany. christian.haass@mail03.med.uni-muenchen.de.

Abstract

Repeat expansion in C9orf72 causes amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Expanded sense and antisense repeat RNA transcripts in C9orf72 are translated into five dipeptide-repeat proteins (DPRs) in an AUG-independent manner. We previously identified the heterogeneous ribonucleoprotein (hnRNP) A3 as an interactor of the sense repeat RNA that reduces its translation into DPRs. Furthermore, we found that hnRNPA3 is depleted from the nucleus and partially mislocalized to cytoplasmic poly-GA inclusions in C9orf72 patients, suggesting that poly-GA sequesters hnRNPA3 within the cytoplasm. We now demonstrate that hnRNPA3 also binds to the antisense repeat RNA. Both DPR production and deposition from sense and antisense RNA repeats are increased upon hnRNPA3 reduction. All DPRs induced DNA double strand breaks (DSB), which was further enhanced upon reduction of hnRNPA3. Poly-glycine-arginine and poly-proline-arginine increased foci formed by phosphorylated Ataxia Telangiectasia Mutated (pATM), a major sensor of DSBs, whereas poly-glycine-alanine (poly-GA) evoked a reduction of pATM foci. In dentate gyri of C9orf72 patients, lower nuclear hnRNPA3 levels were associated with increased DNA damage. Moreover, enhanced poly-GA deposition correlated with reduced pATM foci. Since cytoplasmic pATM deposits partially colocalized with poly-GA deposits, these results suggest that poly-GA, the most frequent DPR observed in C9orf72 patients, differentially causes DNA damage and that poly-GA selectively sequesters pATM in the cytoplasm inhibiting its recruitment to sites of DNA damage. Thus, mislocalization of nuclear hnRNPA3 caused by poly-GA leads to increased poly-GA production, which partially depletes pATM, and consequently enhances DSB.

KEYWORDS:

Amyotrophic lateral sclerosis; C9orf72; DNA damage; Frontotemporal lobar degeneration; Heterogeneous ribonucleoprotein A3; Neurodegeneration

PMID:
31642962
DOI:
10.1007/s00401-019-02082-0

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