Altered cholesterol and fatty acid metabolism in Huntington disease.
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.
Block
Robert C
RC
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. robert_block@urmc.rochester.edu
Dorsey
E Ray
ER
Beck
Christopher A
CA
Brenna
J Thomas
JT
Shoulson
Ira
I
D002490:Central Nervous System / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000178:diet therapy / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance; D050356:Lipid Metabolism; D050505:Mutant Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism
D005227:Fatty Acids; D015525:Fatty Acids, Omega-3; C086055:HTT protein, human; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D002784:Cholesterol
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