Early and brain region-specific decrease of de novo cholesterol biosynthesis in Huntington's disease: A...

Area of Science:

• Neuroscience
• Biochemistry
• Genetics

Background:

• Huntington's disease (HD) is a neurodegenerative disorder.
• Altered cholesterol metabolism is implicated in HD pathogenesis.
• Previous studies indicate reduced cholesterol precursors and levels in HD mouse brains.

Purpose of the Study:

• To quantify the rate of de novo cholesterol biosynthesis in the brain of Huntington's disease (HD) mouse models.
• To investigate the relationship between cholesterol synthesis, CAG repeat size, and disease progression.
• To evaluate 24-hydroxy-cholesterol (24OHC) as a potential biomarker for brain cholesterol metabolism in HD.

Main Methods:

• Utilized the heterozygous knock-in Q175 mouse model for Huntington's disease (HD).
• Quantified cholesterol synthesis rate using 2H2O labeling.
• Measured concentrations of lathosterol, cholesterol, and 24-hydroxy-cholesterol (24OHC) via isotope dilution mass spectrometry in brain regions and blood.

Main Results:

• Significantly reduced cholesterol synthesis rate and lathosterol concentration in the striatum of Q175 mice early in the disease course.
• Inverse correlation between decreased lathosterol and CAG repeat size at the symptomatic stage.
• Significant correlation between fractional synthesis rates of cholesterol and 24OHC, suggesting plasma 24OHC reflects brain cholesterol synthesis.

Conclusions:

• Demonstrated consistent defects in cholesterol biosynthesis in HD mouse models.
• Found that plasma 24OHC may serve as a reliable biomarker for brain cholesterol metabolism in adult individuals.
• Highlights the potential for targeting cholesterol metabolism pathways in HD therapeutics.