7-Dehydrocholesterol (7-DHC) is an important lipid in human biology. It is the immediate biosynthetic precursor of cholesterol and it is also a precursor to vitamin D3. Very recent discoveries indicate that 7-DHC is very prone to undergo free radical chain oxidation with molecular oxygen, i.e. lipid peroxidation. Indeed, 7- DHC's reactivity makes it more susceptible to lipid peroxidation than nearly any other known compound. Lipid peroxidation is associated with many human diseases, including neurodegenerative disorders such as Parkinson's, ALS, Alzheimer's and Huntington's diseases. Many of the compounds formed during lipid peroxidation have potent biological activities and neurodegeneration may be associated with these toxic peroxidation products. A human syndrome affecting 1 in 10-30,000 individuals, Smith-Lemli-Opitz Syndrome (SLOS), is caused by a defect in the enzyme (Dhcr-7) that promotes the last step of cholesterol biosynthesis. This defect results in an increase by up to 10,000-fold of 7-DHC concentrations in individuals suffering from this syndrome. SLOS causes a range of brain abnormalities and these patients also exhibit mental retardation and autism-like symptoms. This proposal is focused on the consequences of the accumulation of 7-DHC in SLOS. A guiding hypothesis is that 7-DHC and its peroxidation metabolites are detrimental to neuronal function. The hypothesis also states that accumulation of 7-DHC and its peroxidation-derived byproducts leads to changes in the growth and function of neurons, the consequences being the devastating abnormalities observed in these individuals. The peroxidation products of 7-DHC have been isolated, purified and fully characterized. Methods will be developed to determine if these peroxidation products or their metabolites are observed as biomarkers in tissues and cells having elevated levels of 7-DHC. The systems studied will include three SLOS mouse models, neuronal cells that are genetically engineered to have high levels of 7-DHC, skin-cells (fibroblasts) from seven SLOS patients and plasma, urine and cerebral spinal fluid from patient samples by Dr. Forbes Porter at the NIH/NICHD. Another major theme of the research is to assess the biological consequences resulting from exposure of a cell or animal to 7-DHC peroxidation products. The effect of peroxidation products on neuronal cell viability, morphology and gene expression will be assessed and finally, an effort will be initiated to find small molecule inhibitors of lipid peroxidation (antioxidants) that protect cells and reverse the phenotypic characteristics of SLOS rodent models. Lipid peroxidation is frequently linked to neurodegenerative disorders and the relevance of this research to public health is the linkage of the fundamental studies in the chemistry and biology of peroxidation and its inhibition proposed here to neurodegenerative disorders, including a devastating syndrome, SLOS.
Smith-Lemli-Opitz syndrome (SLOS) is a devastating neurodevelopmental metabolic disorder caused by a defect in cholesterol biosynthesis that leads to a build up of toxic oxysterol compounds. Establishing assays for the toxic compounds in human fluids and understanding their fundamental neurobiology will shed light on SLOS and lead to therapies for this disorder and others that have altered cholesterol metabolism.
|Dantas, Lucas S; Chaves-Filho, Adriano B; Coelho, Fernando R et al. (2018) Cholesterol secosterol aldehyde adduction and aggregation of Cu,Zn-superoxide dismutase: Potential implications in ALS. Redox Biol 19:105-115|
|Lamberson, Connor R; Muchalski, Hubert; McDuffee, Kari B et al. (2017) Propagation rate constants for the peroxidation of sterols on the biosynthetic pathway to cholesterol. Chem Phys Lipids 207:51-58|
|Korade, Željka; Liu, Wei; Warren, Emily B et al. (2017) Effect of psychotropic drug treatment on sterol metabolism. Schizophr Res 187:74-81|
|Korade, Zeljka; Genaro-Mattos, Thiago C; Tallman, Keri A et al. (2017) Vulnerability of DHCR7+/- mutation carriers to aripiprazole and trazodone exposure. J Lipid Res 58:2139-2146|
|Griffiths, William J; Abdel-Khalik, Jonas; Crick, Peter J et al. (2017) Sterols and oxysterols in plasma from Smith-Lemli-Opitz syndrome patients. J Steroid Biochem Mol Biol 169:77-87|
|Sharif, N F; Korade, Z; Porter, N A et al. (2017) Oxidative stress, serotonergic changes and decreased ultrasonic vocalizations in a mouse model of Smith-Lemli-Opitz syndrome. Genes Brain Behav 16:619-626|
|Tallman, Keri A; Kim, Hye-Young H; Korade, Zeljka et al. (2017) Probes for protein adduction in cholesterol biosynthesis disorders: Alkynyl lanosterol as a viable sterol precursor. Redox Biol 12:182-190|
|Herron, Josi; Reese, Rosalyn C; Tallman, Keri A et al. (2016) Identification of Environmental Quaternary Ammonium Compounds as Direct Inhibitors of Cholesterol Biosynthesis. Toxicol Sci 151:261-70|
|Sever, Navdar; Mann, Randall K; Xu, Libin et al. (2016) Endogenous B-ring oxysterols inhibit the Hedgehog component Smoothened in a manner distinct from cyclopamine or side-chain oxysterols. Proc Natl Acad Sci U S A 113:|
|Korade, Zeljka; Kim, Hye-Young H; Tallman, Keri A et al. (2016) The Effect of Small Molecules on Sterol Homeostasis: Measuring 7-Dehydrocholesterol in Dhcr7-Deficient Neuro2a Cells and Human Fibroblasts. J Med Chem 59:1102-15|
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