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.

Figure 1

A Simplified Overview of the Major Bile-Acid and Neurosteroid Biosynthetic Pathways The bile-acid pathway is indicated in blue, and the neurosteroid pathway is indicated in red.

Figure 2

Family Trees and DNA Sequence Chromatographs Are Indicated by the Red Boxes, and Conservation of Affected Amino Acid Residues Is Shown in the Blue Box