ALS-Linked Protein Blocks Starvation-Induced Autophagy

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https://doi.org/10.1016/j.apsb.2024.02.004

This new article publication from Acta Pharmaceutica Sinica B, discusses how ALS-linked C9orf72 dipeptide repeats inhibit starvation-induced autophagy through modulating BCL2–BECN1 interaction.

Growing evidence indicate that dysfunction of autophagy contributes to the disease pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two neurodegenerative disorders. The GGGGCC·GGCCCC repeat RNA expansion in chromosome 9 open reading frame 72 (C9orf72) is the most genetic cause of both ALS and FTD.

According to previous studies, GGGGCC·GGCCCC repeat undergoes the unconventional repeat-associated non-ATG translation, which produces dipeptide repeat (DPR) proteins. Although there is a growing understanding that C9orf72 DPRs have a strong ability to harm neurons and induce C9orf72-linked ALS/FTD, whether these DPRs can affect autophagy remains unclear.

In this article the authors report that poly-GR and poly-PR, two arginine-containing DPRs which display the most cytotoxic properties according to the previous studies, strongly inhibit starvation-induced autophagy. Moreover, the data indicates that arginine-rich DPRs enhance the interaction between BCL2 and BECN1/Beclin 1 by inhibiting BCL2 phosphorylation, therefore they can impair autophagic clearance of neurodegenerative disease-associated protein aggregates under starvation condition in cells.

This study not only highlights the role of C9orf72 DPR in autophagy dysfunction, but also provides novel insight that pharmacological intervention of autophagy using SW063058, a small molecule compound that can disrupt the interaction between BECN1 and BCL2, may reduce C9orf72 DPR-induced neurotoxicity.

Keywords: Amyotrophic lateral sclerosis, Frontotemporal dementia, C9orf72, Autophagy, BCL2, BECN1/Beclin 1, Dipeptide repeat, Neurodegeneration

Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S221138352400042X-ga1.jpg

ALS/FTD-linked C9orf72 DPRs inhibit starvation-induced autophagy by enhancing BCL2–BECN1/Beclin 1 interaction. Under this condition, pharmacological disruption of the interaction between BECN1 and BCL2 can restore autophagy and may therefore reduce C9orf72 DPR-induced neurotoxicity.

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