TY  - JOUR
AU  - Nihei, Yoshihiro
AU  - Mori, Kohji
AU  - Werner, Georg
AU  - Arzberger, Thomas
AU  - Zhou, Qihui
AU  - Khosravi, Bahram
AU  - Japtok, Julia
AU  - Hermann, Andreas
AU  - Sommacal, Andreas
AU  - Weber, Markus
AU  - Degeneration, German Consortium for Frontotemporal Lobar
AU  - Alliance, Bavarian Brain Banking
AU  - Kamp, Frits
AU  - Nuscher, Brigitte
AU  - Edbauer, Dieter
AU  - Haass, Christian
TI  - Poly-glycine-alanine exacerbates C9orf72 repeat expansion-mediated DNA damage via sequestration of phosphorylated ATM and loss of nuclear hnRNPA3.
JO  - Acta neuropathologica
VL  - 139
IS  - 1
SN  - 0001-6322
CY  - Heidelberg
PB  - Springer
M1  - DZNE-2020-07921
SP  - 99-118
PY  - 2020
AB  - 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.
KW  - Aged
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Ataxia Telangiectasia Mutated Proteins: metabolism
KW  - C9orf72 Protein: genetics
KW  - DNA Damage: genetics
KW  - Dinucleotide Repeats: physiology
KW  - Female
KW  - Frontotemporal Lobar Degeneration: genetics
KW  - Frontotemporal Lobar Degeneration: metabolism
KW  - Heterogeneous-Nuclear Ribonucleoprotein Group A-B: metabolism
KW  - Humans
KW  - Male
KW  - Middle Aged
KW  - Phosphorylation
LB  - PUB:(DE-HGF)16
C6  - pmid:31642962
C2  - pmc:PMC6942035
DO  - DOI:10.1007/s00401-019-02082-0
UR  - https://pub.dzne.de/record/141597
ER  -