Differential Response of C9orf72 Transcripts Following Neuronal Depolarization

Authors

Layla T. Ghaffari, Thomas Jefferson UniversityFollow
Davide Trotti, Thomas Jefferson UniversityFollow
Aaron R. Haeusler, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

5-24-2023

Comments

This article is the author's final published version in iScience, Volume 26, Issue 6, 16 June 2023, Article number 106959.

The published version is available at https://doi.org/10.1016/j.isci.2023.106959. Copyright © 2023 The Authors.

Abstract

The (G4C2)n nucleotide repeat expansion (NRE) mutation in C9orf72 is the most common genetic cause of ALS and FTD. The biological functions of C9orf72 are becoming understood, but it is unclear if this gene is regulated in a neural-specific manner. Neuronal activity is a crucial modifier of biological processes in health and neurodegenerative disease contexts. Here, we show that prolonged membrane depolarization in healthy human iPSC-cortical neurons leads to a significant downregulation of a transcript variant 3 (V3) of C9orf72, with a concomitant increase in variant 2 (V2), which leads to total C9orf72 RNA transcript levels remaining unchanged. However, the same response is not observed in cortical neurons derived from patients with the C9-NRE mutation. These findings reveal the impact of depolarization on C9orf72 transcripts, and how this response diverges in C9-NRE-carriers, which may have important implications in the underlying unique clinical associations of C9-NRE transcripts and disease pathogenesis.

Recommended Citation

Ghaffari, Layla T.; Trotti, Davide; and Haeusler, Aaron R., "Differential Response of C9orf72 Transcripts Following Neuronal Depolarization" (2023). Farber Institute for Neuroscience Faculty Papers. Paper 50.
https://jdc.jefferson.edu/farberneursofp/50

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Language

English