The RNA exosome complex degrades expanded hexanucleotide repeat RNA in C9orf72 FTLD/ALS

Area of Science:

• Molecular Biology
• Neuroscience
• Genetics

Background:

• Nucleotide repeat expansions in the C9orf72 gene are a primary cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS).
• Pathogenic repeat RNA accumulates in RNA foci and is translated into toxic dipeptide repeat proteins (DPRs), but the mechanism of repeat RNA accumulation is not fully understood.

Purpose of the Study:

• To investigate the role of the RNA exosome complex in the degradation of pathogenic C9orf72-derived repeat RNA.
• To elucidate the impact of toxic DPRs on RNA exosome function and repeat RNA metabolism.

Main Methods:

• Knockdown of EXOSC10, the catalytic subunit of the RNA exosome.
• In vitro RNA degradation assays.
• Analysis of repeat RNA and DPR levels in patient-derived cells.

Main Results:

• The RNA exosome complex, particularly EXOSC10, is identified as a major degradation complex for C9orf72 repeat RNA.
• EXOSC10 knockdown leads to increased repeat RNA and DPR protein levels, as well as enhanced RNA foci.
• Arginine-rich DPRs impair EXOSC10 activity, leading to compromised repeat RNA metabolism.

Conclusions:

• The RNA exosome complex plays a critical role in regulating the levels of pathogenic C9orf72 repeat RNA.
• Impairment of the RNA exosome by toxic DPRs contributes to a vicious cycle that exacerbates C9orf72-FTLD/ALS pathology.