RNA Editing of DEGS1 Links Genetic Risk to Ceramide Dysregulation and Astrocyte Toxicity in ALS
- 1Sanofi
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with ~90% of cases being sporadic. Although genome-wide association studies have identified numerous genetic risk loci, these variants account for only a portion of ALS heritability, suggesting that additional genetic and regulatory mechanisms contribute to disease risk. Furthermore, the mechanisms linking common variants to disease pathogenesis remain poorly understood. Adenosine-to-inosine (A-to-I) RNA editing is dysregulated in ALS, yet systematic identification of disease-relevant editing events and their functional consequences has been limited. We performed comprehensive RNA editing analysis across eight central nervous system regions from a Target ALS cohort, identifying 752 differentially edited sites in 304 genes. Global RNA editing was significantly reduced in ALS tissues, particularly in spinal cord and choroid plexus, with altered editing in genes involved in immune signaling, stress response and RNA processing. Through genetic colocalization analysis integrating editing quantitative trait loci (edQTLs) with ALS GWAS data, we identified common variants at the DEGS1 locus associated with both increased 3' UTR editing and elevated ALS risk (posterior probability >0.88). DEGS1 encodes dihydroceramide desaturase 1, a key enzyme converting dihydroceramide to ceramide, the precursor to all sphingolipid species. Using CRISPR-generated DEGS1 knockout iPSCs and lipidomic profiling, we demonstrated that DEGS1 is essential for ceramide synthesis and downstream sphingolipid production in astrocytes. Functional validation revealed that ALS-associated editing of the DEGS1 3' UTR significantly increased DEGS1 protein expression. Critically, astrocytes expressing the fully edited DEGS1 3' UTR increased ceramide levels and reduced cell viability compared to those expressing the unedited construct. These findings establish a novel regulatory link between RNA editing, sphingolipid metabolism and ALS pathogenesis. Our results demonstrate that common genetic variants can influence disease risk through post-transcriptional mechanisms that alter lipid homeostasis in astrocytes, a cell type increasingly recognized as central to ALS progression.
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BibTeX
@misc{guo2026editing,
title = {{RNA Editing of DEGS1 Links Genetic Risk to Ceramide Dysregulation and Astrocyte Toxicity in ALS}},
author = {A. Guo and S. Lessard and L. Guo and M. Li and D. Sood and R. Passaro and J. Huang and C. Chatelain and E. de Rinaldis and S. Khader and B. Zhang and J. C. Dodge and S. Rodriguez},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.17.752108},
url = {https://www.biorxiv.org/content/10.64898/2026.09.17.752108v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - RNA Editing of DEGS1 Links Genetic Risk to Ceramide Dysregulation and Astrocyte Toxicity in ALS
AU - A. Guo
AU - S. Lessard
AU - L. Guo
AU - M. Li
AU - D. Sood
AU - R. Passaro
AU - J. Huang
AU - C. Chatelain
AU - E. de Rinaldis
AU - S. Khader
AU - B. Zhang
AU - J. C. Dodge
AU - S. Rodriguez
PY - 2026
DA - 2026/09/17
PB - bioRxiv
DO - 10.64898/2026.09.17.752108
UR - https://www.biorxiv.org/content/10.64898/2026.09.17.752108v1
AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with ~90% of cases being sporadic. Although genome-wide association studies have identified numerous genetic risk loci, these variants account for only a portion of ALS heritability, suggesting that additional genetic and regulatory mechanisms contribute to disease risk. Furthermore, the mechanisms linking common variants to disease pathogenesis remain poorly understood. Adenosine-to-inosine (A-to-I) RNA editing is dysregulated in ALS, yet systematic identification of disease-relevant editing events and their functional consequences has been limited. We performed comprehensive RNA editing analysis across eight central nervous system regions from a Target ALS cohort, identifying 752 differentially edited sites in 304 genes. Global RNA editing was significantly reduced in ALS tissues, particularly in spinal cord and choroid plexus, with altered editing in genes involved in immune signaling, stress response and RNA processing. Through genetic colocalization analysis integrating editing quantitative trait loci (edQTLs) with ALS GWAS data, we identified common variants at the DEGS1 locus associated with both increased 3' UTR editing and elevated ALS risk (posterior probability >0.88). DEGS1 encodes dihydroceramide desaturase 1, a key enzyme converting dihydroceramide to ceramide, the precursor to all sphingolipid species. Using CRISPR-generated DEGS1 knockout iPSCs and lipidomic profiling, we demonstrated that DEGS1 is essential for ceramide synthesis and downstream sphingolipid production in astrocytes. Functional validation revealed that ALS-associated editing of the DEGS1 3' UTR significantly increased DEGS1 protein expression. Critically, astrocytes expressing the fully edited DEGS1 3' UTR increased ceramide levels and reduced cell viability compared to those expressing the unedited construct. These findings establish a novel regulatory link between RNA editing, sphingolipid metabolism and ALS pathogenesis. Our results demonstrate that common genetic variants can influence disease risk through post-transcriptional mechanisms that alter lipid homeostasis in astrocytes, a cell type increasingly recognized as central to ALS progression.
ER -