C9orf72-mediated ALS and FTD: multiple pathways to disease

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Repeat expansions in the C9orf72 gene are a primary genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
• Understanding the aetiopathogenesis of C9orf72-mediated neurodegenerative diseases is crucial for developing effective therapies.

Purpose of the Study:

• To review the pathological and mechanistic features of C9orf72-associated FTD and ALS (C9FTD/ALS).
• To discuss model systems used for studying these conditions.
• To identify probable initiators of downstream disease mechanisms.

Main Methods:

• Review of existing literature on C9orf72 gene, ALS, and FTD.
• Analysis of proposed disease mechanisms: loss of function, toxic gain of function from repeat RNA, and dipeptide repeat proteins.
• Examination of implicated downstream cellular processes and pathways.

Main Results:

• Three primary disease mechanisms are proposed: C9orf72 protein loss of function, toxic gain of function from repeat RNA, and toxic gain of function from dipeptide repeat proteins.
• Multiple downstream cellular functions are implicated in disease progression.
• Both cell-autonomous and non-cell-autonomous effects contribute to C9FTD/ALS.

Conclusions:

• A combination of upstream loss and gain of function mechanisms drives C9FTD/ALS.
• Downstream cellular pathways, involving both cell-autonomous and non-cell-autonomous effects, are critical for disease progression.
• Further research into these mechanisms and pathways is essential for therapeutic development.