RNA high quality management system goes awry in frontotemporal lobar degeneration

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RNA quality control system goes awry in frontotemporal lobar degeneration

Increased number of C9orf72 repeat RNA foci (aggregated RNA) in a patient-derived cell with decreased expression of an RNA exosome component. Photo credit: Yuya Kawabe, Kohji Mori

Researchers at Osaka University have identified a flaw in the RNA quality control system of cells that leads to the wiring of toxic proteins in frontotemporal lobar degeneration and amyotrophic lateral sclerosis (FTLD / ALS). Their new study, published in the EMBO Journal, shows that an abnormality in the C9orf72 gene produces toxic proteins that hinder cells' ability to destroy defective C9orf72 RNA, resulting in the production of more toxic proteins. Ultimately, a vicious circle arises that accelerates the disease process.

The incurable neurodegenerative diseases FTLD and ALS share genetic traits, including their most common genetic cause: an extension of the repetitive part of the C9orf72 gene. Cells use DNA codes to write instructions for making new proteins in the form of RNA. In C9orf72-associated FTLD / ALS, the repeat DNA is transcribed into defective repeat RNA, which accumulates in the cell and produces toxic proteins.

"Repeated RNA can itself be toxic and is the source of highly toxic protein. Reducing repeated RNA may therefore be a therapeutic option in FTLD / ALS caused by this genetic abnormality," says Kohji Mori, co-author of the study.

The researchers used cell models to study the RNA exosome that is responsible for destroying defective RNA. Damage to EXOSC10, a key player in the RNA exosome, increased the accumulation of repeat RNA and its toxic protein products. Cells with an accumulation of the toxic proteins showed that EXOSC10 function failed. The researchers confirmed the results in cells derived from patients with the disorders and solidified the RNA exosome as a site for the breakdown of pathogenic C9orf72-derived repeat RNA.

"The RNA exosome degrades the defective RNA until it is overwhelmed by the inhibitory effects of the toxic proteins, triggering a downward spiral that can exacerbate neurodegeneration in C9orf72-associated FTLD / ALS," says lead author Yuya Kawabe.

Typically a DNA code is read in one direction, but the repeated expansion in C9orf72 is transcribed bidirectionally. The researchers tested RNA that was transcribed from both directions, known as sense and antisense RNAs. Both RNAs accumulated, produced toxic protein and were degraded by EXOSC10.

The results provide insight into the machinery that drives disease progression at the cellular level. People with FTLD / ALS have few options – no treatment can prevent, cure, or even slow down FTLD / ALS progression. However, this new understanding of the pathological process opens up opportunities to look for therapeutic options.

The article "The RNA Exosome Complex Degrades Expanded Hexanucleotide Repeat RNA in C9orf72 FTLD / ALS" was published in the EMBO Journal

The blood sample can be used to assess the severity and prognosis of frontotemporal lobar degeneration in the future

More information:
Yuya Kawabe et al. The RNA exosome complex degrades expanded hexanucleotide repeat RNA in C9orf72 FTLD / ALS. EMBO J (2020) e102700, doi.org/10.15252/embj.2019102700

Provided by
Osaka University

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