Altered cholesterol and fatty acid metabolism in Huntington disease

Division of Epidemiology, Department of Community and Preventive Medicine and Preventive Cardiology Unit, Box 644, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14620, USA.
Journal of Clinical Lipidology (Impact Factor: 3.59). 02/2010; 4(1):17-23. DOI: 10.1016/j.jacl.2009.11.003
Source: PubMed

ABSTRACT Huntington disease is an autosomal dominant neurodegenerative disorder characterized by behavioral abnormalities, cognitive decline, and involuntary movements that lead to a progressive decline in functional capacity, independence, and ultimately death. The pathophysiology of Huntington disease is linked to an expanded trinucleotide repeat of cytosine-adenine-guanine (CAG) in the IT-15 gene on chromosome 4. There is no disease-modifying treatment for Huntington disease, and novel pathophysiological insights and therapeutic strategies are needed. Lipids are vital to the health of the central nervous system, and research in animals and humans has revealed that cholesterol metabolism is disrupted in Huntington disease. This lipid dysregulation has been linked to specific actions of the mutant huntingtin on sterol regulatory element binding proteins. This results in lower cholesterol levels in affected areas of the brain with evidence that this depletion is pathologic. Huntington disease is also associated with a pattern of insulin resistance characterized by a catabolic state resulting in weight loss and a lower body mass index than individuals without Huntington disease. Insulin resistance appears to act as a metabolic stressor attending disease progression. The fish-derived omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, have been examined in clinical trials of Huntington disease patients. Drugs that combat the dysregulated lipid milieu in Huntington disease may help treat this perplexing and catastrophic genetic disease.


Available from: Tom Brenna, Apr 24, 2015
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    ABSTRACT: Cholesterol is an essential component for neuronal physiology not only during development stage but also in the adult life. Cholesterol metabolism in brain is independent from that in peripheral tissues due to blood-brain barrier. The content of cholesterol in brain must be accurately maintained in order to keep brain function well. Defects in brain cholesterol metabolism has been shown to be implicated in neurodegenerative diseases, such as Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), and some cognitive deficits typical of the old age. The brain contains large amount of cholesterol, but the cholesterol metabolism and its complex homeostasis regulation are currently poorly understood. This review will seek to integrate current knowledge about the brain cholesterol metabolism with molecular mechanisms.
    Protein & Cell 02/2015; 6(4). DOI:10.1007/s13238-014-0131-3 · 2.85 Impact Factor
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    ABSTRACT: Cholesterol is an amphipathic sterol compound that exerts both structural and physiological tasks in the plasma membrane of all eukaryotic cells. The planar and rigid structure of this molecule regulates the fluidity of the phospholipid bilayer and its permeability to solutes and ions. The structural role of cholesterol is particularly relevant in the central nervous system, where it represents one of the major components of myelin sheaths, and an important constituent of the synaptic vesicle membranes. The synthesis and trafficking of cholesterol is highly specialized in the brain, and displays several differences if compared to its metabolism in other tissues. In humans, disruption to cholesterol homeostasis can lead to a wide spectrum of pathological conditions. The relevance of this compound in the pathogenesis of atherosclerosis and other cardiovascular diseases is nowadays well established, while correlations existing between cholesterol and brain disorders are still poorly characterized. Therefore, the aim of this review is to summarize the current knowledge that links alterations of cholesterol homeostasis with the onset and the progression of several neurological and neuropsychiatric disorders.
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    Dataset: 2013 JCP