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The metabolic profile of early Huntington's disease--a combined human and transgenic mouse study
Anna O G Goodman1, Peter R Murgatroyd, Gema Medina-Gomez
1Cambridge Centre for Brain Repair, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge, CB2 2PY, UK. aogr2@cam.ac.uk
Insights
Huntington's disease (HD) patients and mice show early negative energy balance, leading to weight loss and muscle bulk reduction before overt symptoms appear. This metabolic shift may stem from hypothalamic dysfunction in neurodegenerative disease.
Area of Science:
- Neuroscience
- Metabolic Research
- Genetics
Background:
- Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disorder.
- Classical HD symptoms include motor, cognitive, and psychiatric disturbances.
- Unexplained weight loss is common in HD patients, but its timing and cause are unclear.
Purpose of the Study:
- To investigate the metabolic changes, specifically energy balance, in early-stage Huntington's disease.
- To explore the relationship between metabolic alterations and disease progression in both human patients and a mouse model.
- To identify the underlying causes of weight loss in Huntington's disease.
Main Methods:
- Whole-body indirect calorimetry was used to assess metabolism in early-stage HD patients.
- The R6/2 transgenic mouse model of HD was studied before and after disease onset.
- Metabolic parameters were correlated with clinical and pathological signs of disease.
Main Results:
- Early-stage HD patients exhibited a negative energy balance unrelated to motor activity.
- This negative energy balance was mirrored in the R6/2 mouse model.
- Mice showed increased energy expenditure and weight loss, primarily due to muscle atrophy, as the disease progressed.
Conclusions:
- Huntington's disease is characterized by an early-onset negative energy balance.
- This metabolic imbalance may lead to weight loss and muscle loss during disease progression.
- Hypothalamic pathology could be a potential cause of this catabolic state in HD.
Abstract:
Huntington's disease (HD) is a debilitating autosomal dominant, neurodegenerative disease with a fatal prognosis. Classical symptoms include motor disturbances, subcortical dementia and psychiatric symptoms but are not restricted to this triad. Patients often experience other problems such as weight loss, although why and when this occurs in the disease course is not known. We studied metabolism using whole body indirect calorimetry in both early stage HD patients and in the R6/2 transgenic mouse model of HD, at times before and after they displayed signs of disease. Using this combined approach we found that patients with early HD tended to be in negative energy balance for reasons not related to their movement disorder, which was paralleled in the transgenic R6/2 mice. These mice had significantly elevated total energy expenditure as they developed overt disease with weight loss due primarily to a loss of muscle bulk. This study has shown for the first time that in HD there is the development of early negative energy balance, which in turn may cause weight loss with loss of muscle bulk in particular. The reason for this is not known but may reflect a catabolic state secondary to hypothalamic pathology, as abnormalities have been reported in the hypothalamus early in the disease course.
