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Literature summary for 1.14.14.25 extracted from
- CYP46A1, the rate-limiting enzyme for cholesterol degradation, is neuroprotective in Huntingtons disease (2016), Brain, 139, 953-970.
Application
| Application | Comment | Organism |
|---|---|---|
| medicine | restoring CYP46A1 activity in the striatum promises a therapeutic approach in Huntington's disease | Homo sapiens |
Cloned(Commentary)
| Cloned (Comment) | Organism |
|---|---|
| gene CYP46A1, CYP46A1 restoration protects from Exp-HTT-induced striatal dysfunctions in vitro. CYP46A1 restoration in the striatum improves the motor phenotype of R6/2 mice | Mus musculus |
| gene CYP46A1, expression analysis | Homo sapiens |
Protein Variants
| Protein Variants | Comment | Organism |
|---|---|---|
| additional information | knocking down CYP46A1 expression in the striatum, via an adeno-associated virus-mediated delivery of selective shCYP46A1. Expression of shRNA sequence that inhibits CYP46A1 expression in vitro and in vivo, phenotype, overview. CYP46A1 restoration in the striatum improves the motor phenotype of R6/2 mice | Mus musculus |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| cholesterol + [reduced NADPH-hemoprotein reductase] + O2 | Homo sapiens | - |
(24S)-cholest-5-ene-3beta,24-diol + [oxidized NADPH-hemoprotein reductase] + H2O | - |
? |  |
| cholesterol + [reduced NADPH-hemoprotein reductase] + O2 | Mus musculus | - |
(24S)-cholest-5-ene-3beta,24-diol + [oxidized NADPH-hemoprotein reductase] + H2O | - |
? | |
| cholesterol + [reduced NADPH-hemoprotein reductase] + O2 | Mus musculus C57BL/6 | - |
(24S)-cholest-5-ene-3beta,24-diol + [oxidized NADPH-hemoprotein reductase] + H2O | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | Q9Y6A2 | - |
- |
| Mus musculus | Q9WVK8 | and R6/2 mutant mice | - |
| Mus musculus C57BL/6 | Q9WVK8 | and R6/2 mutant mice | - |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| brain | - |
Mus musculus | - |
| brain | neuronal-specific CYP46A1 protein levels are decreased in the putamen, but not cerebral cortex samples, of post-mortem Huntington's disease patients when compared to controls | Homo sapiens | - |
| cerebral cortex | - |
Homo sapiens | - |
| additional information | R6/2 mice express exon 1 of the human mutant Huntingtons disease gene containing 160 CAG repeats, under control of the human HTT (IT15) promoter | Mus musculus | - |
| neuron | - |
Homo sapiens | - |
| neuron | - |
Mus musculus | - |
| putamen | - |
Homo sapiens | - |
| striatum | - |
Homo sapiens | - |
| striatum | Cyp46A1 mRNA and CYP46A1 protein levels are decreased in the striatum of the R6/2 Huntington's disease mouse model and in SThdhQ111 cell lines | Mus musculus | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| cholesterol + [reduced NADPH-hemoprotein reductase] + O2 | - |
Homo sapiens | (24S)-cholest-5-ene-3beta,24-diol + [oxidized NADPH-hemoprotein reductase] + H2O | - |
? | |
| cholesterol + [reduced NADPH-hemoprotein reductase] + O2 | - |
Mus musculus | (24S)-cholest-5-ene-3beta,24-diol + [oxidized NADPH-hemoprotein reductase] + H2O | - |
? | |
| cholesterol + [reduced NADPH-hemoprotein reductase] + O2 | - |
Mus musculus C57BL/6 | (24S)-cholest-5-ene-3beta,24-diol + [oxidized NADPH-hemoprotein reductase] + H2O | - |
? | |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| CYP46A1 | - |
Homo sapiens |
| CYP46A1 | - |
Mus musculus |
Cofactor
| Cofactor | Comment | Organism | Structure |
|---|---|---|---|
| heme | - |
Mus musculus | |
| NADPH | - |
Homo sapiens | |
| NADPH | - |
Mus musculus | |
General Information
| General Information | Comment | Organism |
|---|---|---|
| malfunction | CYP46A1 expression levels are reduced in Huntington's disease. CYP46A1 protein levels are decreased in the putamen, but not cerebral cortex samples, of post-mortem Huntington's disease patients when compared to controls. Huntington's disease is an autosomal dominant neurodegenerative disease caused by abnormal polyglutamine expansion in huntingtin leading to degeneration of striatal neurons. Altered brain cholesterol homeostasis is implicated in Huntington's disease, with increased accumulation of cholesterol in striatal neurons yet reduced levels of cholesterol metabolic precursors | Homo sapiens |
| malfunction | knocking down CYP46A1 expression in the striatum, via an adeno-associated virus-mediated delivery of selective shCYP46A1, reproduced the Huntingtons disease phenotype, with spontaneous striatal neuron degeneration and motor deficits. CYP46A1 expression levels are reduced in Huntington's disease. In the R6/2 Huntington's disease mouse model, adeno-associated virus-mediated delivery of CYP46A1 into the striatum decreases neuronal atrophy, decreases the number, intensity level and size of expansion in huntingtin aggregates and improves motor deficits, as assessed by rotarod and clasping behavioural tests. Adeno-associated virus-CYP46A1 infection in R6/2 mice also restores levels of cholesterol and lanosterol and increases levels of desmosterol | Mus musculus |
| physiological function | cholesterol 24-hydroxylase is the neuronal-specific and rate-limiting enzyme for cholesterol conversion to 24S-hydroxycholesterol, regulation of cholesterol homeostasis by CYP46A1 | Homo sapiens |
| physiological function | cholesterol 24-hydroxylase is the neuronal-specific and rate-limiting enzyme for cholesterol conversion to 24S-hydroxycholesterol, regulation of cholesterol homeostasis by CYP46A1. In vitro, CYP46A1 restoration protects SThdhQ111 and Exp-HTT-expressing striatal neurons in culture from cell death | Mus musculus |
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