Altered Phase Separation and Cellular Impact in C9orf72-Linked ALS/FTD

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• The C9orf72 repeat expansion mutation is a primary genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
• Cellular compartmentalization via liquid-liquid phase separation (LLPS) is crucial for forming membraneless organelles.

Purpose of the Study:

• To review the principles of phase separation in the context of C9orf72-ALS/FTD.
• To discuss how C9orf72-associated dipeptide repeat proteins (DPRs) and repeat RNA perturb physiological LLPS.
• To explore the impact of abnormal phase separation on TDP-43 proteinopathy and potential therapeutic strategies.

Main Methods:

• Review of existing literature on C9orf72, LLPS, and neurodegenerative diseases.
• Analysis of the role of DPRs and repeat RNA in phase separation.
• Discussion of the functional consequences of perturbed LLPS in C9orf72-ALS/FTD.

Main Results:

• Toxic DPRs and repeat RNA, translated from the C9orf72 mutation, undergo aberrant phase separation.
• This abnormal phase separation disrupts the formation and function of essential membraneless organelles.
• Perturbed LLPS contributes to cellular dysfunction and pathological hallmarks like TDP-43 proteinopathy.

Conclusions:

• Abnormal phase separation is a key pathogenic mechanism in C9orf72-linked ALS and FTD.
• Targeting aberrant LLPS presents a potential therapeutic avenue for C9orf72-ALS/FTD.