1. C9ORF72 dipeptide repeat poly-GA inclusions promote intracellular aggregation of phosphorylated TDP-43.
- Author
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Nonaka T, Masuda-Suzukake M, Hosokawa M, Shimozawa A, Hirai S, Okado H, and Hasegawa M
- Subjects
- Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis pathology, Cells, Cultured, DNA Repeat Expansion, Dipeptides genetics, Dipeptides metabolism, Frontotemporal Lobar Degeneration genetics, Frontotemporal Lobar Degeneration pathology, Humans, Phosphorylation, Polyglutamic Acid metabolism, Repetitive Sequences, Amino Acid, alpha-Synuclein metabolism, tau Proteins metabolism, C9orf72 Protein genetics, C9orf72 Protein metabolism, DNA-Binding Proteins metabolism
- 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., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2018
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