Life science
Healthcare, Drug discovery

Elucidation of the mechanism of abnormally expanded repeat RNA accumulation and developmentof novel therapeutic strategies thereof in frontotemporal dementia
Department of Psychiatry, Graduate School of Medicine
Assistant Professor Kohji Mori

Researchmap https://researchmap.jp/kmori_psy/?lang=en

Professor Manabu Ikeda

Researchmap https://researchmap.jp/manabu_ikeda?lang=en

Life science

Abstract

metabolism or inhibiting its translation into repeat proteins.

Frontotemporal dementia (FTD) is a neurocognitive disorder withprominent neurodegeneration in the frontal and temporal lobes, resulting in behavioral abnormalities, personality changes, and aphasia, and is a frequent cause of early-onset dementia. Aberrantly expanded repeats in the introns of the C9orf72 (chromosome 9 openreading frame 72) gene cause two intractable diseases: frontotemporal dementia (also called frontotemporal lobar degeneration) andamyotrophic lateral sclerosis (ALS). In this study, we revealed that
expanded repeat RNAs derived from the mutated C9orf72 geneare degraded by an RNA-degrading enzyme complex called theRNA exosome. In addition, we showed that repeat proteins, thatare produced (translated) from the repeat RNA by a non-canonicalmechanism, suppresses the activity of the RNA exosome and accelerates the accumulation of the pathogenic repeat RNA.

▍ Background & Results
So far, no treatments can cure FTD/ALS, or even slow its progression. The expanded tandem DNA repeats are transcribed into
repeat RNA, which often forms RNA aggregates in the cell (Figure1). In addition, we have previously shown that the C9orf72 repeat
RNA undergoes atypical translation to produce repeat proteins thatabundantly accumulate in neurons. Repeat RNA can be toxic itself
and is the source of highly toxic repeat protein.
Although it was known that aberrantly elongated repeat RNAs
accumulated in patient derived C9orf72 mutant cells, it was notclear by what mechanism the repeat RNAs were degraded or escaped degradation and accumulated in the cells. Using diseasemodel cells, we revealed that the repeat RNA is degraded intracellularly by RNA exosomes. Furthermore, we found that the arginine
containing repeat protein, which is produced by repeat associated
non-AUG translation (RAN translation) of the repeat RNA, inhibits
the activity of RNA exosomes and thus suppresses the degradationof the aberrant repeat RNA, resulting in the accumulation of moreaberrant repeat RNA in the cell.

▍ Significance of the research and Future perspective
Our findings provide potential avenues to explore for therapyoptions. The intracellular accumulation of repeat RNA due to abnormal RNA degradation would leads to increased production ofhighly toxic repeat proteins, which in turn results in neurodegeneration. Since mutations in RNA exosome components cause anotherneurological disease called pontocerebellar hypoplasia, it is possible that abnormal RNA metabolism due to RNA exosome disruption by repeat proteins itself modifies the pathophysiology of FTD/
ALS. Taking these into account, reducing repeat RNA by restoring/augmenting the activity of RNA exosome complex could be a therapeutic option in FTD/ALS caused by this genetic abnormality. Ourgroup aims to develop novel therapies by promoting repeat RNA

P a t e n t US10066007
Mori, Kohji; Gotoh, Shiho; Yamashita, Tomoko et al. The porphyrin TMPyP4 inhibits elongation during the non-canonical translation of the FTLD/ALS-associated GGGGCC repeat in the C9orf72 gene. Journal of Biological Chemistry.
2021; 297(4): 101120. doi: 10.1016/j.jbc.2021.101120
Tr e a t i s e
Kawabe, Yuya; Mori, Kohji; Yamashita, Tomoko et al. The RNA exosome complex degrades expanded hexanucleotide repeat RNA in C9orf72 FTLD / ALS. The EMBO Journal. 2020; 39(19): e102700. doi:10.15252/embj.2019102700
Mori, Kohji; Weng, Shih-Ming; Arzberger, Thomas et al. The C9orf72 GGGGCC Repeat Is Translated into Aggregating Dipeptide-Repeat Proteins in FTLD/ALS. Science. 2013; 339(6125): 1335-8. doi: 10.1126/science.1232927
https://resou.osaka-u.ac.jp/ja/research/2020/20200827_2
URL https://www.med.osaka-u.ac.jp/activities/results/2020year/mori-20200827
http://first.lifesciencedb.jp/archives/6559
K e y w o r d frontotemporal dementia, frontotemporal lobar degeneration, RNA, RAN translation