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

Acta Neuropathol.

2019 Oct 23. doi: 10.1007/s00401-019-02082-0.

Yoshihiro Nihei, Kohji Mori, Georg Werner, Thomas Arzberger, Qihui Zhou, Barham Khosravi, Julia Japtok, Andreas HermannAndreas Sommacal, Markus Webe, German Consortium for Frontotemporal Lobar Degeneration, Bavarian Brain Banking Alliance, Frits Kamp, Brigitte Nusche, rDieter Edbauer, Christian Haass

An abnormal expansion of a hexanucleotide (GGGGCC) repeat sequence in intron 1 of the C9orf72 gene is the most common genetic mutation in sporadic and familial amyotrophic lateral sclerosis and frontotemporal dementia in Caucasians. This abnormal expansion produces five types of dipeptide repeat proteins (DPRs) through repeat-associated non-AUG (RAN) translation, which does not require a start codon, and these are thought to play a crucial role in neurotoxicity. In this study, we confirmed that poly-GA, the most frequently observed DPR in patient brains, captures pATM, which plays a key role in the repair of DNA double-strand breaks (DSBs), in the cytoplasm, thereby inhibiting its translocation into the nucleus. Furthermore, poly-GA also colocalizes in the cytoplasm with hnRNPA3, which is thought to be involved in the degradation of repeat RNA. The resulting decrease in nuclear hnRNPA3 is believed to cause a further increase in the expression of repeat RNA and DPRs. This vicious cycle is thought to exacerbate DSB repair dysfunction, leading to neuronal cell death. These findings are considered important for the development of therapeutic strategies targeting DNA repair dysfunction.

(Yoshihiro Nihei, Department of Neurology (Class of '83 equivalent), studying abroad at DZNE Munich, Germany)