Journal Article

C9ORF72 dipeptide repeat poly-GA inclusions promote intracellular aggregation of phosphorylated TDP-43

Takashi Nonaka, Masami Masuda-Suzukake, Masato Hosokawa, Aki Shimozawa, Shinobu Hirai, Haruo Okado and Masato Hasegawa

in Human Molecular Genetics

Volume 27, issue 15, pages 2658-2670
Published in print August 2018 | ISSN: 0964-6906
Published online May 2018 | e-ISSN: 1460-2083 | DOI:

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Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are neurodegenerative diseases characterized by accumulation of insoluble aggregates of phosphorylated 43 kDa TAR DNA-binding protein (TDP-43) and linked with abnormal expansion of a hexanucleotide repeat in an intron of chromosome 9 open reading frame 72 (C9ORF72). However, the relationship between C9ORF72 mutations and TDP-43 aggregation remains unknown. Non-ATG-dependent translation of C9ORF72 repeats produces dipeptide repeat proteins, which form p62-positive aggregates in cerebral cortex and cerebellum of patients. Here, we show that the formation of poly-GA protein inclusions induced intracellular aggregation of endogenous and exogenous TDP-43 in cultured cells. Poly-GA aggregation preceded accumulation of phosphorylated TDP-43. These inclusions induced intracellular aggregation of phosphorylated TDP-43, but not tau or α-synuclein. Formation of phosphorylated TDP-43 aggregates depends on the number of poly-GA repeats. Detergent-insoluble fraction from cells co-expressing poly-GA and TDP-43 could function as seeds for further TDP-43 aggregation. These findings suggest a novel pathogenic mechanism that poly-GA protein aggregation directly promotes pathogenic changes of TDP-43 without the formation of nuclear RNA foci containing GGGGCC repeat expansion or loss-of-function of the C9ORF72 protein.

Journal Article.  6065 words.  Illustrated.

Subjects: Genetics and Genomics