Title: The role of seladin-1/DHCR24 in cholesterol biosynthesis, APP processing and A beta generation in vivo
Authors: Crameri, A
Biondi, E
Kuehnle, K
Lutjohann, D
Thelen, KM
Perga, S
Dotti, Carlos
Nitsch, RM
Ledesma, MD
Mohajeri, MH #
Issue Date: Jan-2006
Series Title: Embo Journal vol:25 issue:2 pages:432-443
Abstract: The cholesterol-synthesizing enzyme seladin-1, encoded by the Dhcr24 gene, is a flavin adenine dinucleotide-dependent oxidoreductase and regulates responses to oncogenic and oxidative stimuli. It has a role in neuroprotection and is downregulated in affected neurons in Alzheimer's disease (AD). Here we show that seladin-1-deficient mouse brains had reduced levels of cholesterol and disorganized cholesterol-rich detergent-resistant membrane domains (DRMs). This was associated with inefficient plasminogen binding and plasmin activation, the displacement of beta-secretase ( BACE) from DRMs to APP-containing membrane fractions, increased beta-cleavage of APP and high levels of A beta peptides. In contrast, overexpression of seladin-1 increased both cholesterol and the recruitment of DRM components into DRM fractions, induced plasmin activation and reduced both BACE processing of APP and A beta formation. These results establish a role of seladin-1 in the formation of DRMs and suggest that seladin-1-dependent cholesterol synthesis is involved in lowering A beta levels. Pharmacological enhancement of seladin-1 activity may be a novel A beta-lowering approach for the treatment of AD.
ISSN: 0261-4189
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Genetics Section (-)
Department of Human Genetics - miscellaneous
# (joint) last author

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