C9orf72 Toxic Species Affect ArfGAP-1 Function

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Nucleocytoplasmic transport is crucial for cellular function.
• Defects in this transport are implicated in neurodegenerative diseases like ALS.
• C9orf72 repeat expansions are the leading genetic cause of ALS and disrupt transport.

Purpose of the Study:

• To identify specific mRNAs mislocalized due to C9orf72 repeat expansions.
• To investigate the impact of C9orf72 toxicity on cellular transport pathways.
• To elucidate the mechanism by which C9orf72 affects nucleocytoplasmic distribution.

Main Methods:

• Expression of G4C2 hexanucleotide repeats in human and mouse cells.
• Systematic identification of altered mRNAs using transcriptomic analysis.
• Functional studies in cultured cells and Drosophila models.
• Investigation of ADP-Ribosylation Factor 1 GTPase Activating Protein (ArfGAP-1) function.

Main Results:

• Accumulation of poly(A) mRNAs in cell nuclei was observed.
• mRNAs involved in membrane trafficking were significantly enriched among mislocalized RNAs.
• C9orf72 toxic species, including RNA repeats and dipeptide repeat proteins (C9-DPRs), impair ArfGAP-1 function.
• Retrograde Golgi-to-ER vesicle-mediated transport was identified as a target of C9orf72 toxicity.

Conclusions:

• C9orf72 repeat expansions disrupt nucleocytoplasmic transport, leading to mRNA mislocalization.
• The membrane trafficking pathway regulated by ArfGAP-1 is a key target of C9orf72 toxicity in ALS.
• Understanding this mechanism provides insights into ALS pathogenesis and potential therapeutic strategies.