Sphingolipid remodelling in SPT-related neuropathies

Abstract

Sphingolipid homeostasis is critical for neuronal structural and functional integrity in the central and peripheral nervous systems. The rate-limiting enzyme of this pathway, serine-palmitoyltransferase (SPT), establishes the metabolic entry point into sphingolipid biosynthesis. Mutations in the SPT subunits, SPTLC1 and SPTLC2 lead to contrasting disease phenotypes in patients, including amyotrophic lateral sclerosis (ALS) and hereditary sensory neuropathy (HSAN1). A third mixed sensory-motor phenotype is attributed to distinct mutation sets in SPTLC1 and SPTLC2. However, a direct comparison of the metabolic consequences of mutations spanning these disease conditions has not been performed. Here, we demonstrate that SPTLC1- and SPTLC2-ALS variants contribute to enhanced sphingolipid flux while the ceramide-mediated homeostatic control is impaired. In contrast, HSAN1-associated variants display altered substrate selectivity, shifting flux towards non-canonical 1-deoxysphingolipid (1-deoxySL) production but decreasing canonical synthesis. The variant associated with a mixed sensory-motor phenotype exhibit a third metabolic state with elevated 1-deoxySL formation and, in contrast to HSAN1-variants, increased canonical sphingolipid synthesis. Sphingolipid profiling reveals that ALS variants are characterized by preferential accumulation of dihydro- and intermediate chain sphingolipid species. Notably, the separation of lipid species between ALS and HSAN1 is robust, with canonical sphingolipids enriched in ALS variants, while long-chain 1-deoxySL dominate in HSAN1. The SPT-variants associated with mixed sensory and motor symptoms are associated with elevated levels of both types. The data support the view that segregated shifts in sphingolipid flux underlie divergence of clinical phenotypes in SPT-variants and offer guidance for therapeutic interventions. Importantly, therapeutic strategies must account for these metabolic configurations, as L-serine supplementation may benefit HSAN1 but exacerbate pathology in ALS and sensory-motor disease conditions.