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An iPSC model of hereditary sensory neuropathy-1 reveals L-serine-responsive deficits in neuronal ganglioside composition and axoglial interactions

Hereditary sensory neuropathy type 1 (HSN1) is caused by mutations in the SPTLC1 or SPTLC2 sub-units of the enzyme serine palmitoyltransferase, resulting in the production of toxic 1-deoxysphingolipid bases (DSBs). We used induced pluripotent stem cells (iPSCs) from patients with HSN1 to determine w...

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Autores principales: Clark, Alex J., Kugathasan, Umaiyal, Baskozos, Georgios, Priestman, David A., Fugger, Nadine, Lone, Museer A., Othman, Alaa, Chu, Ka Hing, Blesneac, Iulia, Wilson, Emma R., Laurà, Matilde, Kalmar, Bernadett, Greensmith, Linda, Hornemann, Thorsten, Platt, Frances M., Reilly, Mary M., Bennett, David L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324498/
https://www.ncbi.nlm.nih.gov/pubmed/34337561
http://dx.doi.org/10.1016/j.xcrm.2021.100345
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author Clark, Alex J.
Kugathasan, Umaiyal
Baskozos, Georgios
Priestman, David A.
Fugger, Nadine
Lone, Museer A.
Othman, Alaa
Chu, Ka Hing
Blesneac, Iulia
Wilson, Emma R.
Laurà, Matilde
Kalmar, Bernadett
Greensmith, Linda
Hornemann, Thorsten
Platt, Frances M.
Reilly, Mary M.
Bennett, David L.
author_facet Clark, Alex J.
Kugathasan, Umaiyal
Baskozos, Georgios
Priestman, David A.
Fugger, Nadine
Lone, Museer A.
Othman, Alaa
Chu, Ka Hing
Blesneac, Iulia
Wilson, Emma R.
Laurà, Matilde
Kalmar, Bernadett
Greensmith, Linda
Hornemann, Thorsten
Platt, Frances M.
Reilly, Mary M.
Bennett, David L.
author_sort Clark, Alex J.
collection PubMed
description Hereditary sensory neuropathy type 1 (HSN1) is caused by mutations in the SPTLC1 or SPTLC2 sub-units of the enzyme serine palmitoyltransferase, resulting in the production of toxic 1-deoxysphingolipid bases (DSBs). We used induced pluripotent stem cells (iPSCs) from patients with HSN1 to determine whether endogenous DSBs are neurotoxic, patho-mechanisms of toxicity and response to therapy. HSN1 iPSC-derived sensory neurons (iPSCdSNs) endogenously produce neurotoxic DSBs. Complex gangliosides, which are essential for membrane micro-domains and signaling, are reduced, and neurotrophin signaling is impaired, resulting in reduced neurite outgrowth. In HSN1 myelinating cocultures, we find a major disruption of nodal complex proteins after 8 weeks, which leads to complete myelin breakdown after 6 months. HSN1 iPSC models have, therefore, revealed that SPTLC1 mutation alters lipid metabolism, impairs the formation of complex gangliosides, and reduces axon and myelin stability. Many of these changes are prevented by l-serine supplementation, supporting its use as a rational therapy.
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spelling pubmed-83244982021-07-31 An iPSC model of hereditary sensory neuropathy-1 reveals L-serine-responsive deficits in neuronal ganglioside composition and axoglial interactions Clark, Alex J. Kugathasan, Umaiyal Baskozos, Georgios Priestman, David A. Fugger, Nadine Lone, Museer A. Othman, Alaa Chu, Ka Hing Blesneac, Iulia Wilson, Emma R. Laurà, Matilde Kalmar, Bernadett Greensmith, Linda Hornemann, Thorsten Platt, Frances M. Reilly, Mary M. Bennett, David L. Cell Rep Med Article Hereditary sensory neuropathy type 1 (HSN1) is caused by mutations in the SPTLC1 or SPTLC2 sub-units of the enzyme serine palmitoyltransferase, resulting in the production of toxic 1-deoxysphingolipid bases (DSBs). We used induced pluripotent stem cells (iPSCs) from patients with HSN1 to determine whether endogenous DSBs are neurotoxic, patho-mechanisms of toxicity and response to therapy. HSN1 iPSC-derived sensory neurons (iPSCdSNs) endogenously produce neurotoxic DSBs. Complex gangliosides, which are essential for membrane micro-domains and signaling, are reduced, and neurotrophin signaling is impaired, resulting in reduced neurite outgrowth. In HSN1 myelinating cocultures, we find a major disruption of nodal complex proteins after 8 weeks, which leads to complete myelin breakdown after 6 months. HSN1 iPSC models have, therefore, revealed that SPTLC1 mutation alters lipid metabolism, impairs the formation of complex gangliosides, and reduces axon and myelin stability. Many of these changes are prevented by l-serine supplementation, supporting its use as a rational therapy. Elsevier 2021-07-21 /pmc/articles/PMC8324498/ /pubmed/34337561 http://dx.doi.org/10.1016/j.xcrm.2021.100345 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Clark, Alex J.
Kugathasan, Umaiyal
Baskozos, Georgios
Priestman, David A.
Fugger, Nadine
Lone, Museer A.
Othman, Alaa
Chu, Ka Hing
Blesneac, Iulia
Wilson, Emma R.
Laurà, Matilde
Kalmar, Bernadett
Greensmith, Linda
Hornemann, Thorsten
Platt, Frances M.
Reilly, Mary M.
Bennett, David L.
An iPSC model of hereditary sensory neuropathy-1 reveals L-serine-responsive deficits in neuronal ganglioside composition and axoglial interactions
title An iPSC model of hereditary sensory neuropathy-1 reveals L-serine-responsive deficits in neuronal ganglioside composition and axoglial interactions
title_full An iPSC model of hereditary sensory neuropathy-1 reveals L-serine-responsive deficits in neuronal ganglioside composition and axoglial interactions
title_fullStr An iPSC model of hereditary sensory neuropathy-1 reveals L-serine-responsive deficits in neuronal ganglioside composition and axoglial interactions
title_full_unstemmed An iPSC model of hereditary sensory neuropathy-1 reveals L-serine-responsive deficits in neuronal ganglioside composition and axoglial interactions
title_short An iPSC model of hereditary sensory neuropathy-1 reveals L-serine-responsive deficits in neuronal ganglioside composition and axoglial interactions
title_sort ipsc model of hereditary sensory neuropathy-1 reveals l-serine-responsive deficits in neuronal ganglioside composition and axoglial interactions
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324498/
https://www.ncbi.nlm.nih.gov/pubmed/34337561
http://dx.doi.org/10.1016/j.xcrm.2021.100345
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