Abstract
Huntington’s disease (HD) is a neurodegenerative illness, where selective neuronal loss in the brain caused by expression of mutant huntingtin protein leads to motor dysfunction and cognitive decline in addition to peripheral metabolic changes. In this study we confirm our previous observation of impairment of lactate-based hepatic gluconeogenesis in the transgenic HD mouse model R6/2 and determine that the defect manifests very early and progresses in severity with disease development, indicating a potential to explore this defect in a biomarker context. Moreover, R6/2 animals displayed lower blood glucose levels during prolonged fasting compared to wild type animals.
Highlights
Huntington’s disease (HD) is neurological disease caused by a dominant trinucleotide expansion mutation (CAG) in the huntingtin gene leading to a dominant gain of function of the mutant huntingtin protein[1]
In order to characterize the development of these changes, relative to the development of symptoms of HD, we performed a longitudinal study of blood lactate and glucose levels after a lactate challenge in R6/2 mice at 4, 6, 8 and 10 weeks of age (n = Wild type (WT): 5 males + 6 females, R6/2: 7 males + 5 females)
Lactate conversion deteriorates with age in the R6/2 mice compared to control animals as shown by total area under curve (AUC) and peak concentration of blood lactate and glucose after a lactate challenge (WT: 5 males + 6 females, R6/2: 7 males + 5 females)
Summary
Huntington’s disease (HD) is neurological disease caused by a dominant trinucleotide expansion mutation (CAG) in the huntingtin gene leading to a dominant gain of function of the mutant huntingtin protein (mHTT)[1]. Due to neuronal cell loss in specific brain regions, the striatum, patients experience motor dysfunction, cognitive decline as well as psychiatric symptoms[2]. There is currently no known cure for the disease. A CAG repeat length expansion of 39 or more is sufficient to cause HD1,3. The huntingtin gene is globally expressed, and mHTT accumulates over time, forming cellular inclusions[4,5]. In addition to the neuropathological changes characterizing HD, peripheral cell dysfunction is widespread[6]
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