title: Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration.
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.
authors.affiliation: Medical Genetics, Clinical Developmental Sciences, St George's University of London, Cranmer Terrace, London, SW17 0RE, UK.
authors.forename: Maria K
authors.initials: MK
authors.lastname: Tsaousidou
authors.forename: Karim
authors.initials: K
authors.lastname: Ouahchi
authors.forename: Tom T
authors.initials: TT
authors.lastname: Warner
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.forename: Nigel G
authors.initials: NG
authors.lastname: Laing
authors.forename: Philip A
authors.initials: PA
authors.lastname: Wilkinson
authors.forename: Ricardo E
authors.initials: RE
authors.lastname: Madrid
authors.forename: Heema
authors.initials: H
authors.lastname: Patel
authors.forename: Faycal
authors.initials: F
authors.lastname: Hentati
authors.forename: Michael A
authors.initials: MA
authors.lastname: Patton
authors.forename: Afif
authors.initials: A
authors.lastname: Hentati
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Lamont
authors.forename: Teepu
authors.initials: T
authors.lastname: Siddique
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Crosby
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002784:Cholesterol / Q000378:metabolism*; D002874:Chromosome Mapping; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072474:Cytochrome P450 Family 7; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000378:metabolism; D008969:Molecular Sequence Data; D010375:Pedigree; D017422:Sequence Analysis, DNA; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics*
chemical_list: D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D013250:Steroid Hydroxylases; D000072474:Cytochrome P450 Family 7; C499571:CYP7B1 protein, human