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Review
. 2023 Jan 16;6(1):9-15.
doi: 10.31662/jmaj.2022-0160. Epub 2022 Dec 23.

RNA Dysmetabolism and Repeat-Associated Non-AUG Translation in Frontotemporal Lobar Degeneration/Amyotrophic Lateral Sclerosis due to C9orf72 Hexanucleotide Repeat Expansion

Kohji Mori  1 , Shiho Gotoh  1 , Ryota Uozumi  1 , Tesshin Miyamoto  1   2 , Shoshin Akamine  1 , Yuya Kawabe  1   3 , Shinji Tagami  3   4 , Manabu Ikeda  1
Affiliations
Review

RNA Dysmetabolism and Repeat-Associated Non-AUG Translation in Frontotemporal Lobar Degeneration/Amyotrophic Lateral Sclerosis due to C9orf72 Hexanucleotide Repeat Expansion

Kohji Mori et al. JMA J. .

Abstract

Neuropathological features of frontotemporal dementia and amyotrophic lateral sclerosis (ALS) due to C9orf72 GGGGCC hexanucleotide repeat expansion include early dipeptide repeats, repeat RNA foci, and subsequent TDP-43 pathologies. Since the discovery of the repeat expansion, extensive studies have elucidated the disease mechanism of how the repeat causes neurodegeneration. In this review, we summarize our current understanding of abnormal repeat RNA metabolism and repeat-associated non-AUG translation in C9orf72 frontotemporal lobar degeneration/ALS. For repeat RNA metabolism, we specifically focus on the role of hnRNPA3, the repeat RNA-binding protein, and the EXOSC10/RNA exosome complex, an intracellular RNA-degrading enzyme. In addition, the mechanism of repeat-associated non-AUG translation inhibition via TMPyP4, a repeat RNA-binding compound, is discussed.

Keywords: C9orf72; Frontotemporal dementia; RNA metabolism; Repeat-associated non-AUG translation; amyotrophic lateral sclerosis; frontotemporal lobar degeneration.

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Conflict of interest statement

None

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