Sequence Alterations within CYP7B1 Implicate Defective Cholesterol Homeostasis in Motor-Neuron Degeneration

Maria K. Tsaousidou, Karim Ouahchi, Tom T. Warner, Yi Yang, Michael A. Simpson, Nigel G G. Laing, Philip A. Wilkinson, Ricardo E. Madrid, Heema Patel, Faycal Hentati, Michael A A. Patton, Afif Hentati, Philippa J. Lamont, Teepu Siddique, Andrew H. Crosby*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

126 Scopus citations

Abstract

The hereditary spastic paraplegias (HSPs) are a genetically and clinically heterogeneous group of upper-motor-neuron degenerative diseases characterized by selective axonal loss in the corticospinal tracts and dorsal columns. Although numerous mechanisms involving defective subcellular transportation, mitochondrial malfunction, and increased oxidative stress have been proposed, the pathogenic basis underlying the neuronal loss is unknown. We have performed linkage analysis to refine the extent of the SPG5 disease locus and conducted sequence analysis of the genes located within this region. This identified sequence alterations in the cytochrome P450-7B1 (CYP7B1) associated with this pure form of HSP. In the liver, CYP7B1 offers an alternative pathway for cholesterol degradation and also provides the primary metabolic route for the modification of dehydroepiandrosterone neurosteroids in the brain. These findings provide the first direct evidence of a pivotal role of altered cholesterol metabolism in the pathogenesis of motor-neuron degenerative disease and identify a potential for therapeutic intervention in this form of HSP.

Original languageEnglish (US)
Pages (from-to)510-515
Number of pages6
JournalAmerican journal of human genetics
Volume82
Issue number2
DOIs
StatePublished - Feb 8 2008

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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