Background Huntington disease (HD) a progressive brain dysfunction and degeneration caused by characterised by CAG repeat expansion mutation, that is translated into results polyglutamine tract in huntingtin (Htt), a protein whose size-dependent toxicity influences age at onset. Mutant Htt (mHtt) interferes with several essential biologic processes, including defective energy metabolism. Glucose is the primary source of metabolic energy for the brain and defects in glucose utilisation can virtually affect brain activities.
Aim Our first aim was to test whether basal glucose metabolism in subjects with a genetic risk of HD may influence onset of manifest symptoms. Second we proposed to investigate how glucose levels might modulate neuronal vulnerability to dysfunction in presence of mHtt.
Methods Functional study in HD patients. 43 presymptomatic HD subjects underwent 18F-FDG PET scan and prospectively followed up for at least 5 years. Clinical changes were detected by using the unified HD rating scale.
In vitro study Mouse striatal-derived cells expressing mHtt (STHdh111/111) were cultured in absence or in presence of different concentrations of glucose. Cell survival was then determined by Annexin V staining.
Results Of the 43 preHD subjects who manifested motor symptoms, after 5 years from 18F-FDG PET scan, 26 showed a loss of glucose utilisation in the caudate, that was significantly lower than the 17 preHD subjects who remained symptoms-free (p<0.0001). This difference was independent of mutation size. Measurement of brain glucose uptake improved CAG repeat number and age-based model for predicting age at onset by 37 %. In addition, data from in vitro experiments indicate that reduced levels of glucose enhance susceptibility to apoptosis in HD cells.
Conclusion Reduced glucose metabolism exerts an important impact on neuronal function and in the brain caudate may represent a predisposing factor that contributes to the age at onset of HD in preHD subjects.
- glucose metabolism
- cell survival
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