Differential response of C9orf72 transcripts following neuronal depolarization

Layla T Ghaffari; Davide Trotti; Aaron R Haeusler

doi:10.1016/j.isci.2023.106959

Differential response of C9orf72 transcripts following neuronal depolarization

iScience. 2023 May 24;26(6):106959. doi: 10.1016/j.isci.2023.106959. eCollection 2023 Jun 16.

Authors

Layla T Ghaffari¹, Davide Trotti¹, Aaron R Haeusler¹

Affiliation

¹ Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, USA.

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.

Keywords: Cell biology; Molecular biology; Neuroscience.

Abstract

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