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Measuring RAN Peptide Toxicity in C. elegans

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Published on: April 30, 2020

C9orf72 Toxic Species Affect ArfGAP-1 Function.

Simona Rossi^1,2, Michela Di Salvio³, Marilisa Balì⁴

¹Institute of Translational Pharmacology (IFT), National Research Council (CNR), 00133 Rome, Italy.

|August 11, 2023

Summary

Defects in nucleocytoplasmic transport, particularly from C9orf72 repeat expansions, disrupt RNA distribution in ALS. This study reveals that toxic C9orf72 species impair membrane trafficking by affecting ArfGAP-1 function.

Keywords:

ArfGAP-1 C9orf72 Drosophila melanogaster Golgi-to-ER trafficking amyotrophic lateral sclerosis

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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.