Evidence for altered cholesterol metabolism in Huntington's disease post mortem brain tissue.
Level 4 - case-series / case-control
Case-control study of post-mortem human brain tissue
PubMed 26373857 · doi:10.1111/nan.12286
What was done
Gas chromatography-tandem mass spectrometry was used to measure cholesterol precursors, metabolites, and oxidation products across five brain regions from human post-mortem Huntington's disease (HD) tissue compared with age- and sex-matched controls. Expression of the cholesterol-regulating enzymes cholesterol 24-hydroxylase and delta(24)-sterol reductase was examined in the putamen using Western blotting and qPCR.
What was found
The most significant changes were detected in the HD putamen: a 60% decrease in 24(S)-hydroxycholesterol, a 30% increase in cholesterol, a 100% to 200% increase in synthetic precursors (lathosterol, zymosterol, and desmosterol), significant decreases in cholesterol 24-hydroxylase and delta(24)-sterol reductase, and a 50% to 70% increase in free radical-generated cholesterol oxidation products (7-keto cholesterol and 7β-hydroxycholesterol). Specific quantitative values for the other four brain regions were not reported in the abstract.
Why it matters
This study provides direct human post-mortem evidence that cholesterol synthesis, metabolism, and homeostasis are altered in Huntington's disease, with marked lipid oxidative stress present in the putamen.
Limits
The sample size is not stated in the abstract. As a cross-sectional post-mortem study, it cannot establish whether altered cholesterol metabolism is a primary driver or a secondary consequence of end-stage neurodegeneration.
Cited by
- contradicts In the central nervous system, cholesterol synthesis occurs exclusively through the desmosterol pathway, making circulating desmosterol a proxy for brain cholesterol synthesis, whereas lathosterol reflects peripheral cholesterol synthesis.