Marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis

Rebecca Schüle, S. Siddique, Xiang Deng, Yi Yang, Sandra Donkervoort, Magnus Hansson, Ricardo E. Madrid, Nailah Siddique, Ludger Schöls, Ingemar Björkhem*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

Abstract

Patients with a recessively inherited "pure" hereditary spastic paresis (SPG5) have mutations in the gene coding for the oxysterol 7 α hydroxylase (CYP7B1). One of the expected metabolic consequences of such mutations is accumulation of oxysterol substrates due to decreased enzyme activity. In accordance with this, we demonstrate here that four patients with the SPG5 disease have 6-to 9-fold increased plasma levels of 27-hydroxycholesterol. A much higher increase, 30-to 50-fold, was found in cerebrospinal fl uid. The plasma levels of 25-hydroxycholesterol were increased about 100-fold. There were no measurable levels of this oxysterol in cerebrospinal fluid. The pattern of bile acids in serum was normal, suggesting a normal bile acid synthesis. The fi ndings are discussed in relation to two transgenic mouse models with increased levels of 27-hydroxycholesterol in the circulation but without neurological symptoms: the cyp27a1 transgenic mouse and the cyp7b1 knockout mouse. The absolute plasma levels of 27-hydroxycholesterol in the latter models are, however, only about 20% of those in the SPG5 patients. If the accumulation of 27-hydroxycholesterol is an important pathogenetic factor, a reduction of its levels may reduce or prevent the neurological symptoms. A possible strategy to achieve this is discussed.

Original languageEnglish (US)
Pages (from-to)819-823
Number of pages5
JournalJournal of lipid research
Volume51
Issue number4
DOIs
StatePublished - Apr 1 2010

Keywords

  • 25-hydroxycholesterol
  • 27-hydroxycholesterol
  • CYP27A1
  • Neurodegeneration
  • Oxysterol

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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