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

Abstract

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.

• Authors: Takashi Nonaka, Masami Masuda-Suzukake, Masato Hosokawa, Aki Shimozawa, Shinobu Hirai, Haruo Okado, Masato Hasegawa
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 27 Issue 15 Pg. 2658-2670 (08 01 2018) ISSN: 1460-2083 [Electronic] England
• PMID: 29750243 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected].

Chemical References

• C9orf72 Protein
• C9orf72 protein, human
• DNA-Binding Proteins
• Dipeptides
• TARDBP protein, human
• alpha-Synuclein
• tau Proteins
• Polyglutamic Acid

Topics

• Amyotrophic Lateral Sclerosis (genetics, pathology)
• C9orf72 Protein (genetics, metabolism)
• Cells, Cultured
• DNA Repeat Expansion
• DNA-Binding Proteins (metabolism)
• Dipeptides (genetics, metabolism)
• Frontotemporal Lobar Degeneration (genetics, pathology)
• Humans
• Phosphorylation
• Polyglutamic Acid (metabolism)
• Repetitive Sequences, Amino Acid
• alpha-Synuclein (metabolism)
• tau Proteins (metabolism)