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

Human Molecular Genetics
Takashi NonakaMasato Hasegawa

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 pathogeni...Continue Reading

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Mar 17, 2020·The EMBO Journal·Bahram KhosraviDieter Edbauer
Feb 19, 2019·Behavioural Neurology·Mirjana Babić LekoGoran Šimić
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Apr 2, 2021·The EMBO Journal·Maria Elena CicardiDavide Trotti
May 21, 2021·Eye and Brain·Vladislav O SoldatovAlexey V Deykin
Apr 1, 2020·Biochemical and Biophysical Research Communications·Laurent BrasseurLuc Bousset

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