Activity of partially inhibited serine palmitoyltransferase is sufficient for normal sphingolipid metabolism and viability of HSN1 patient cells

Vadim N. Dedov*, Irina V. Dedova, Alfred H. Merrill, Garth A. Nicholson

*Corresponding author for this work

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Hereditary sensory neuropathy type I (HSN1) is a common degenerative disorder of peripheral sensory neurons. HSN1 is caused by mutations in the gene, encoding the long chain base 1 of serine palmitoyltransferase (SPT) [Nat. Genet. 27 (2001) 309]. Here, we show a 44% reduction of SPT activity in transformed lymphocytes from HSN1 patients with mutation T399G in the SPTLC1 gene. However, the decrease in SPT activity had no effect on de novo sphingolipid biosynthesis, cellular sphingolipid content, cell proliferation and death (apoptosis and necrosis). The removal of extracellular sphingolipids did not affect viability of HSN1 cells. We also found no significant difference in whole blood counts, viability, and permeability to Triton X-100 of primary lymphocytes from HSN1 patients. These results suggest that, despite the inhibition of mutant allele, the activity of nonmutant allele of STP may be sufficient for adequate sphingolipid biosynthesis and cell viability. Therefore, the neurodegeneration in HSN1 is likely to be caused by subtler and rather long-term effect(s) of these mutations such as loss of a cell-type selective facet of sphingolipid metabolism and/or function, or perhaps accumulation of toxic species, including abnormal protein(s) as in other neurodegenerations.

Original languageEnglish
Pages (from-to)168-175
Number of pages8
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1688
Issue number2
DOIs
Publication statusPublished - 2 Mar 2004
Externally publishedYes

Keywords

  • 3- ketodehydrosphinganine
  • 3KDS
  • Cell death
  • Cell proliferation
  • EBV
  • Epstein-Barr virus
  • Hereditary sensory neuropathy
  • HSN1
  • Human sensory neuropathy type I
  • ISP-1
  • Myriocin
  • PI
  • Propidium iodide
  • Serine palmitoyltransferase
  • Sphingolipid
  • Transformed lymphocyte

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