Proteome alterations associated with the V144D SPTLC1 mutation that causes hereditary sensory neuropathy-I

Background: Hereditary sensory neuropathy type is the most common subtype and presents with clinical onset in the second to third decade of life with progressive degeneration of the dorsal root ganglion neurons. Three different missense mutations in the gene encoding for serine palmitoyltransferase long chain subunit 1 have been linked to HSN-I. Here we quantitatively assess the proteomes and identify marked protein alterations in both mitochondria and endoplasmic reticulum from HSN-I patient lymphoblasts which harbour the V144D mutation. Methods: Mitochondria and endoplasmic reticulum were fractionated and lysed from control and patient-derived lymphoblasts. Protein samples were separated into total soluble and total membrane fractions and analysed using a well-established topdown proteomic protocol. Altered protein species were identified by LC MS/MS. Results: Using a detailed proteomic approach, we identified 36 proteins that were completely altered in abundance in cells harbouring the V144D SPTLC1 mutation relative to normal controls. Conclusion: The data establish that major protein alterations occur in both the endoplasmic reticulum, where the SPTLC1 protein resides, and in the mitochondria from V144D patient lymphoblasts. These proteins potentially play a major role in disease pathogenesis and may thus help to further elucidate the molecular mechanism(s) underlying hereditary sensory neuropathy type I and might also prove to be potential therapeutic targets.