Advertisement

ResearchIn-Press PreviewNeuroscience Open Access | 10.1172/JCI161908

SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins

Museer A. Lone,1 Mari J. Aaltonen,2 Aliza Zidell,3 Helio F. Pedro,3 Jonas A. Morales Saute,4 Shalett Mathew,1 Payam Mohassel,5 Carsten G. Bonnemann,5 Eric A. Shoubridge,2 and Thorsten Hornemann1

1Institute of Clinical Chemistry, University of Zurich, Zurich, Switzerland

2Montreal Neurological Institute, McGill University, Montreal, Canada

3Center for Genetic and Genomic Medicine, Hackensack University Medical Center, Hackensack, United States of America

4Medical Genetics Division and Neurology Division, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

5Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America

Find articles by Lone, M. in: JCI | PubMed | Google Scholar |

1Institute of Clinical Chemistry, University of Zurich, Zurich, Switzerland

2Montreal Neurological Institute, McGill University, Montreal, Canada

3Center for Genetic and Genomic Medicine, Hackensack University Medical Center, Hackensack, United States of America

4Medical Genetics Division and Neurology Division, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

5Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America

Find articles by Aaltonen, M. in: JCI | PubMed | Google Scholar |

1Institute of Clinical Chemistry, University of Zurich, Zurich, Switzerland

2Montreal Neurological Institute, McGill University, Montreal, Canada

3Center for Genetic and Genomic Medicine, Hackensack University Medical Center, Hackensack, United States of America

4Medical Genetics Division and Neurology Division, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

5Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America

Find articles by Zidell, A. in: JCI | PubMed | Google Scholar

1Institute of Clinical Chemistry, University of Zurich, Zurich, Switzerland

2Montreal Neurological Institute, McGill University, Montreal, Canada

3Center for Genetic and Genomic Medicine, Hackensack University Medical Center, Hackensack, United States of America

4Medical Genetics Division and Neurology Division, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

5Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America

Find articles by Pedro, H. in: JCI | PubMed | Google Scholar

1Institute of Clinical Chemistry, University of Zurich, Zurich, Switzerland

2Montreal Neurological Institute, McGill University, Montreal, Canada

3Center for Genetic and Genomic Medicine, Hackensack University Medical Center, Hackensack, United States of America

4Medical Genetics Division and Neurology Division, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

5Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America

Find articles by Morales Saute, J. in: JCI | PubMed | Google Scholar |

1Institute of Clinical Chemistry, University of Zurich, Zurich, Switzerland

2Montreal Neurological Institute, McGill University, Montreal, Canada

3Center for Genetic and Genomic Medicine, Hackensack University Medical Center, Hackensack, United States of America

4Medical Genetics Division and Neurology Division, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

5Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America

Find articles by Mathew, S. in: JCI | PubMed | Google Scholar

1Institute of Clinical Chemistry, University of Zurich, Zurich, Switzerland

2Montreal Neurological Institute, McGill University, Montreal, Canada

3Center for Genetic and Genomic Medicine, Hackensack University Medical Center, Hackensack, United States of America

4Medical Genetics Division and Neurology Division, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

5Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America

Find articles by Mohassel, P. in: JCI | PubMed | Google Scholar |

1Institute of Clinical Chemistry, University of Zurich, Zurich, Switzerland

2Montreal Neurological Institute, McGill University, Montreal, Canada

3Center for Genetic and Genomic Medicine, Hackensack University Medical Center, Hackensack, United States of America

4Medical Genetics Division and Neurology Division, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

5Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America

Find articles by Bonnemann, C. in: JCI | PubMed | Google Scholar |

1Institute of Clinical Chemistry, University of Zurich, Zurich, Switzerland

2Montreal Neurological Institute, McGill University, Montreal, Canada

3Center for Genetic and Genomic Medicine, Hackensack University Medical Center, Hackensack, United States of America

4Medical Genetics Division and Neurology Division, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

5Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America

Find articles by Shoubridge, E. in: JCI | PubMed | Google Scholar

1Institute of Clinical Chemistry, University of Zurich, Zurich, Switzerland

2Montreal Neurological Institute, McGill University, Montreal, Canada

3Center for Genetic and Genomic Medicine, Hackensack University Medical Center, Hackensack, United States of America

4Medical Genetics Division and Neurology Division, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

5Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States of America

Find articles by Hornemann, T. in: JCI | PubMed | Google Scholar |

Published July 28, 2022 - More info

J Clin Invest. https://doi.org/10.1172/JCI161908.
Copyright © 2022, Lone et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 28, 2022 - Version history
View PDF
Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. Mutations in the SPTLC1 subunit of serine-palmitoyltransferase (SPT), which catalyzes the first step in the de novo synthesis of sphingolipids cause childhood-onset ALS. SPTLC1-ALS variants map to a transmembrane domain that interacts with ORMDL proteins, negative regulators of SPT activity. We show that ORMDL binding to the holoenzyme complex is impaired in cells expressing pathogenic SPTLC1-ALS alleles, resulting in increased sphingolipid synthesis and a distinct lipid signature. C-terminal SPTLC1 variants cause the peripheral sensory neuropathy HSAN1 due to the synthesis of 1-deoxysphingolipids (1-deoxySLs) that form when SPT metabolizes L-alanine instead of L-serine. Limiting L-serine availability in SPTLC1-ALS expressing cells increased 1-deoxySL and shifted the SL profile from an ALS to an HSAN1-like signature. This effect was corroborated in an SPTLC1-ALS pedigree in which the index patient uniquely presented with an HSAN1 phenotype, increased 1-deoxySL levels, and an L-serine deficiency. These data demonstrate how pathogenic variants in different domains of SPTLC1 give rise to distinct clinical presentations that are nonetheless modifiable by substrate availability.

Graphical Abstract
graphical abstract
Supplemental material

View

Version history
  • Version 1 (July 28, 2022): In-Press Preview
Advertisement
Advertisement