Enhanced deoxysphingobase production in HSN1 results in sensory nerve toxicity through deficits in both cell autonomous and axoglial signalling, ameliorated by serine treatment

Hereditary sensory neuropathy type 1 (HSN1) is caused by mutations in either the SPTLC1 or SPTLC2 sub-units of the enzyme Serine Palmitoyl Transferase resulting in the production of Deoxyshingobases (DSBs). Exogenous DSBs are toxic when acutely applied to neurons however it’s unknown whether endogenous DSBs are neurotoxic and the mechanism of such toxicity. Using induced pleuripotent stem cells (iPSC) from HSN1 patients we found increased DSB production from both hepatocytes and sensory neurons. Gene expression profiling in HSN1 iPSCd-sensory neurons showed dysregulation in axon outgrowth and lipid signalling pathways. We noted reduced lipid raft formation, impaired growth factor signalling and reduced neurite outgrowth in these neurons. Gangliosides which are essential for membrane dynamics and lipid raft formation and were globally reduced due to feedback inhibition of DSBs on the enzyme… In co-cultures between HSN1 iPSCd-sensory neurons and rat Schwann the nodal complex and myelin were disrupted. HSN1 SPTLC mutations therefor impair cell autonomous and inter-cellular signalling due to altered lipid metabolism, changes which could largely be prevented by treatment with Serine (which reduces DSB production) supporting Serine as a rational therapy.