SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFRGS |
Texto Completo: | http://hdl.handle.net/10183/250482 |
Resumo: | Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons. Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT), which catalyzes the first step in the de novo synthesis of sphingolipids (SLs), 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 SL synthesis and a distinct lipid signature. C-terminal SPTLC1 variants cause peripheral hereditary sensory and autonomic neuropathy type 1 (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. |
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Lone, Museer A.Aaltonen, Mari J.Zidell , AlizaPedro, Helio F.Saute, Jonas Alex MoralesMathew, ShalettMohassel, PayamBönnemann, Carsten G.Shoubridge, Eric A.Hornemann, Thorsten2022-10-27T04:52:22Z20220021-9738http://hdl.handle.net/10183/250482001152103Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons. Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT), which catalyzes the first step in the de novo synthesis of sphingolipids (SLs), 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 SL synthesis and a distinct lipid signature. C-terminal SPTLC1 variants cause peripheral hereditary sensory and autonomic neuropathy type 1 (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.application/pdfengThe Journal of clinical investigation. New York, NY. Vol. 132, no. 18 (Nov. 2011), e161908, p. 1-12Esclerose amiotrófica lateralMetabolismo dos carboidratosDoenças neuromuscularesNeurociênciasALSCarbohydrate metabolismNeuromuscular diseaseNeuroscienceSPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteinsEstrangeiroinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFRGSinstname:Universidade Federal do Rio Grande do Sul (UFRGS)instacron:UFRGSTEXT001152103.pdf.txt001152103.pdf.txtExtracted Texttext/plain62902http://www.lume.ufrgs.br/bitstream/10183/250482/2/001152103.pdf.txtc93d474367578a81ea65d30151b51ec8MD52ORIGINAL001152103.pdfTexto completo (inglês)application/pdf7826025http://www.lume.ufrgs.br/bitstream/10183/250482/1/001152103.pdf0c158fee56ed156d8c860761a74229e7MD5110183/2504822023-09-13 03:32:46.20082oai:www.lume.ufrgs.br:10183/250482Repositório de PublicaçõesPUBhttps://lume.ufrgs.br/oai/requestopendoar:2023-09-13T06:32:46Repositório Institucional da UFRGS - Universidade Federal do Rio Grande do Sul (UFRGS)false |
dc.title.pt_BR.fl_str_mv |
SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins |
title |
SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins |
spellingShingle |
SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins Lone, Museer A. Esclerose amiotrófica lateral Metabolismo dos carboidratos Doenças neuromusculares Neurociências ALS Carbohydrate metabolism Neuromuscular disease Neuroscience |
title_short |
SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins |
title_full |
SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins |
title_fullStr |
SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins |
title_full_unstemmed |
SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins |
title_sort |
SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins |
author |
Lone, Museer A. |
author_facet |
Lone, Museer A. Aaltonen, Mari J. Zidell , Aliza Pedro, Helio F. Saute, Jonas Alex Morales Mathew, Shalett Mohassel, Payam Bönnemann, Carsten G. Shoubridge, Eric A. Hornemann, Thorsten |
author_role |
author |
author2 |
Aaltonen, Mari J. Zidell , Aliza Pedro, Helio F. Saute, Jonas Alex Morales Mathew, Shalett Mohassel, Payam Bönnemann, Carsten G. Shoubridge, Eric A. Hornemann, Thorsten |
author2_role |
author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Lone, Museer A. Aaltonen, Mari J. Zidell , Aliza Pedro, Helio F. Saute, Jonas Alex Morales Mathew, Shalett Mohassel, Payam Bönnemann, Carsten G. Shoubridge, Eric A. Hornemann, Thorsten |
dc.subject.por.fl_str_mv |
Esclerose amiotrófica lateral Metabolismo dos carboidratos Doenças neuromusculares Neurociências |
topic |
Esclerose amiotrófica lateral Metabolismo dos carboidratos Doenças neuromusculares Neurociências ALS Carbohydrate metabolism Neuromuscular disease Neuroscience |
dc.subject.eng.fl_str_mv |
ALS Carbohydrate metabolism Neuromuscular disease Neuroscience |
description |
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons. Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT), which catalyzes the first step in the de novo synthesis of sphingolipids (SLs), 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 SL synthesis and a distinct lipid signature. C-terminal SPTLC1 variants cause peripheral hereditary sensory and autonomic neuropathy type 1 (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. |
publishDate |
2022 |
dc.date.accessioned.fl_str_mv |
2022-10-27T04:52:22Z |
dc.date.issued.fl_str_mv |
2022 |
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Estrangeiro info:eu-repo/semantics/article |
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0021-9738 |
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001152103 |
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http://hdl.handle.net/10183/250482 |
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dc.relation.ispartof.pt_BR.fl_str_mv |
The Journal of clinical investigation. New York, NY. Vol. 132, no. 18 (Nov. 2011), e161908, p. 1-12 |
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info:eu-repo/semantics/openAccess |
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