RNA Misprocessing in C9orf72-Linked Neurodegeneration

Area of Science:

• Genetics and Molecular Biology
• Neurodegenerative Diseases
• RNA Biology

Background:

• The GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is the leading genetic cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).
• C9orf72-associated ALS/FTD presents with diverse clinical features and involves complex misregulated cellular pathways.
• Altered RNA processing is a central pathological mechanism in C9orf72-associated ALS/FTD.

Purpose of the Study:

• To review and consolidate current knowledge on the impact of the C9orf72 repeat expansion on RNA processing.
• To highlight the mechanisms by which C9orf72 molecular pathology perturbs RNA metabolism at all stages.
• To draw attention to the multifaceted nature of RNA misprocessing in C9orf72-associated ALS/FTD.

Main Methods:

• Literature review and synthesis of existing research findings on C9orf72 gene, RNA processing, ALS, and FTD.
• Analysis of studies investigating RNA metabolism alterations, including transcription, splicing, localization, translation, and degradation.
• Examination of repeat-associated non-AUG (RAN) translation and its role in dipeptide repeat protein (DPR) formation.

Main Results:

• The C9orf72 repeat expansion leads to bidirectional transcription, nuclear RNA foci formation, and RAN translation producing DPRs.
• Disruptions are observed across the entire lifecycle of RNA molecules, from transcription release to degradation.
• Specific alterations in C9orf72 RNA processing, including transcription, splicing, and subcellular localization, are identified.

Conclusions:

• The C9orf72 repeat expansion profoundly impacts multiple facets of RNA processing, contributing significantly to ALS and FTD pathogenesis.
• Understanding these RNA processing defects is crucial for elucidating the molecular mechanisms underlying C9orf72-associated neurodegeneration.
• Further research into the convergence of these molecular pathologies may reveal novel therapeutic targets for ALS and FTD.