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

Alex J Clark,Umaiyal Kugathasan,Georgios Baskozos,David A Priestman,Nadine Fugger,Museer A Lone,Alaa Othman,Ka Hing Chu,Iulia Blesneac,Emma R Wilson,Matilde Laurà,Bernadett Kalmar,Linda Greensmith,Thorsten Hornemann,Frances M Platt,Mary M Reilly,David L Bennett

doi:10.1016/j.xcrm.2021.100345

Abstract

SummaryHereditary 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.

Highlights

Hereditary sensory neuropathy type 1 (HSN1) is the most common sub-type of HSN and is a disabling neuropathy associated with profound sensory loss, neuropathic pain, and ulceration of the extremities with variable motor involvement.[1,2,3,4] in most cases neurophysiology and neuropathology are consistent with an axonal sensory motor neuropathy, in some cases, there is slowing of conduction and segmental demyelination, suggesting defects in myelination and/or the nodal complex.[1]
Exogenous and endogenous deoxysphingolipid bases (DSBs) are toxic to human iPSCd sensory neurons We first assessed the effect of exogenous DSBs added to culture medium of human induced pluripotent stem cell-derived sensory neurons from healthy control subjects
We found that 1-deoxySA and 1-deoxymeSA were highly neurotoxic over a rapid timescale; 48-hour treatment of 3week-old control iPSCdSNs with both metabolites resulted in a dose-dependent, significant increase in the expression of the injury marker ATF317 (Figure S2)

Summary

Introduction

Hereditary sensory neuropathy type 1 (HSN1) is the most common sub-type of HSN and is a disabling neuropathy associated with profound sensory loss, neuropathic pain, and ulceration of the extremities with variable motor involvement.[1,2,3,4] in most cases neurophysiology and neuropathology are consistent with an axonal sensory motor neuropathy, in some cases (especially in males), there is slowing of conduction and segmental demyelination, suggesting defects in myelination and/or the nodal complex.[1] HSN1 is due to heterozygous missense mutations in the genes SPTLC13,4 or SPTLC25 encoding two subunits of the enzyme serine palmitoyltransferase (SPT) This enzyme catalyzes de novo formation of sphingoid bases (SBs), which are a class of lipids that form the backbone of all sphingolipids (SLs). SLs are terminally degraded after phosphorylation of the C1–OH group by the sphingosine phosphate lyase 1 (SGPL1) (Figure S1)

Methods

Results

Discussion

Conclusion