Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration.
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.
Tsaousidou
Maria K
MK
Medical Genetics, Clinical Developmental Sciences, St George's University of London, Cranmer Terrace, London, SW17 0RE, UK.
Ouahchi
Karim
K
Warner
Tom T
TT
Yang
Yi
Y
Simpson
Michael A
MA
Laing
Nigel G
NG
Wilkinson
Philip A
PA
Madrid
Ricardo E
RE
Patel
Heema
H
Hentati
Faycal
F
Patton
Michael A
MA
Hentati
Afif
A
Lamont
Philippa J
PJ
Siddique
Teepu
T
Crosby
Andrew H
AH
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*
D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D013250:Steroid Hydroxylases; D000072474:Cytochrome P450 Family 7; C499571:CYP7B1 protein, human