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Published on: March 25, 2020
Study of cholesterol metabolism in Huntington's disease
Valerio Leoni1, Claudio Caccia1
1Laboratory of Clinical Pathology and Medical Genetics, Foundation IRCCS Institute of Neurology Carlo Besta, Milano, Italy.
Insights
Huntington's disease disrupts cholesterol metabolism, impacting brain cells and leading to reduced cholesterol levels. This dysregulation correlates with disease severity and neurodegeneration.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Huntington's disease (HD) is a neurodegenerative disorder caused by CAG repeat expansion in the huntingtin gene.
- HD is characterized by striatal and cortical neurodegeneration, often visible as brain atrophy on MRI.
- Previous studies indicate altered cholesterol metabolism in HD models.
Purpose of the Study:
- To investigate the role of huntingtin in regulating cholesterol metabolism.
- To explore the impact of mutant huntingtin on cholesterol synthesis and transport pathways.
- To correlate biochemical findings with disease progression in humans.
Main Methods:
- Analysis of gene expression related to cholesterol biosynthesis in HD mouse models.
- Measurement of cholesterol and related sterol levels in brain tissues.
- Assessment of SREBP maturation, LXR activity, and ApoE-mediated cholesterol transport.
- Evaluation of PGC1α function in oligodendrocytes and Myelin Basic Protein expression.
- Correlation of plasma 24S-hydroxycholesterol levels with clinical and MRI findings in human HD patients.
Main Results:
- Reduced expression of cholesterol biosynthetic genes (e.g., HMG-CoA reductase) and lower levels of key sterols (cholesterol, lanosterol, lathosterol, 24S-hydroxycholesterol) in HD mouse brains.
- Mutant huntingtin impairs SREBP processing and LXR activation, hindering cholesterol synthesis and astrocyte-to-neuron transport via ApoE.
- Inhibition of PGC1α's regulatory role on cholesterol metabolism and Myelin Basic Protein expression in primary oligodendrocytes.
- Decreased plasma 24S-hydroxycholesterol levels in human HD patients correlate with disease progression, motor/neuropsychiatric symptoms, and brain atrophy.
Conclusions:
- Huntingtin plays a crucial regulatory role in lipid metabolism, particularly cholesterol homeostasis.
- Dysregulation of PGC1α and mitochondrial dysfunction contribute to impaired cholesterol synthesis and energy deficits (Acetyl-CoA, ATP) in HD.
- These metabolic disturbances likely contribute to the widespread cerebral and systemic impairments observed in Huntington's disease.
Abstract:
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an abnormal expansion of a CAG repeat in the huntingtin gene. Neurodegeneration of striatum and cortex with a severe atrophy at MRI are common findings in HD. The expression of genes involved in the cholesterol biosynthetic pathway such as HMG-CoA reductase and the levels of cholesterol, lanosterol, lathosterol and 24S-hydroxycholesterol are reduced in the brain, striatum and cortex in several HD mouse models. Mutant huntingtin affects the maturation and translocation of SREBP and cannot up-regulate LXR. There is a lower synthesis and transport of cholesterol from astrocytes to neurons via ApoE. In primary oligodendrocytes, mutant huntingtin inhibits the regulatory effect of PGC1α on cholesterol metabolism and the expression of Myelin Basic Protein. In humans the decrease of plasma 24S-hydroxycholesterol follows disease progression proportionally to motor and neuropsychiatric dysfunctions and MRI brain atrophy. Huntingtin seems to play a regulatory role in lipid metabolism. Dysregulation of PGC1α and mitochondrial dysfunction may reduce synthesis of Acetyl-CoA and ATP contributing to the cerebral and whole body impairment of cholesterol metabolism.
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