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

Clark, AJ; Kugathasan, U; Baskozos, G; Priestman, DA; Fugger, N; Lone, MA; Othman, A; ... Bennett, DL; + view all (2021) An iPSC model of hereditary sensory neuropathy-1 reveals L-serine-responsive deficits in neuronal ganglioside composition and axoglial interactions. Cell Reports Medicine , 2 (7) , Article 10034. 10.1016/j.xcrm.2021.100345. Green open access

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Abstract

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.

Type: Article
Title: An iPSC model of hereditary sensory neuropathy-1 reveals L-serine-responsive deficits in neuronal ganglioside composition and axoglial interactions
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.xcrm.2021.100345
Publisher version: https://doi.org/10.1016/j.xcrm.2021.100345
Language: English
Additional information: © 2021 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: hereditary sensory neuropathy type 1, HSN1, serine palmitoyltransferase, SPT, serine palmitoyltransferase long-chain base subunit 1, SPTLC1, 1-deoxySLBs, DSBs, sphingolipid, ganglioside, sensory neuron, myelin, axon, l-serine
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10132384
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