biostudies-literatureClark AJBrain Research UKNINDS NIH HHSRosetreesWellcome Trust100345https://www.ebi.ac.uk/biostudies/studies/S-EPMC8324498biostudies-literatureUnknown2(7)Hereditary sensory neuropathy type 1 (HSN1) is caused by mutations in the <i>SPTLC1</i> or <i>SPTLC2</i> 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 brCell reports. MedicineAn iPSC model of hereditary sensory neuropathy-1 reveals L-serine-responsive deficits in neuronal ganglioside composition and axoglial interactions.PMC8324498203141/Z/16/ZU54 NS065712M861202747/Z/16/Z202834/Z/16/Z102645/Z/13/Z201718-11Fugger NKalmar BKugathasan UBennett DLOthman AGreensmith LChu KHHornemann TClark AJReilly MMBaskozos GBlesneac ILaura MLone MAPriestman DAPlatt FMWilson ERfalseAn 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 <i>SPTLC1</i> or <i>SPTLC2</i> 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 br2021-01-01T00:00:00Z2021 Jul2026-05-08T14:33:17.29Z2022-02-11T02:18:10.873ZS-EPMC83244983433756110.1016/j.xcrm.2021.100345