Huntington's disease (HD) is an autosomal dominant genetic neurological disorder, caused by an expansion in the CAG region of the human huntingtin gene (HTT). This mutation causes a toxic gain of function to the encoded mutant huntingtin protein (mHTT), which is expressed ubiquitously in both peripheral tissues and the brain. mHTT expression levels are highest in the CNS, and the striatum, cortex, and hypothalamus are most severely affected. HD typically onsets in midlife and consist of severe motor, cognitive, psychiatric, and metabolic symptoms, which worsen over 10-15 years and always lead to death. In human HD patients and in transgenic HD mice there is a robust, significant elevation in circulating glucocorticoid levels. Human HD patients show a two-fold elevation of serum cortisol and transgenic HD mice show a six-fold elevation in corticosterone, the rodent homolog of cortisol. The causes and consequences of this elevation is largely uncharacterized. However, there is recent evidence showing that elevated corticosterone in rodent HD models exacerbates cognitive deficits, causes neuropathological changes, worsens the metabolic phenotype, and hastens time to death. Additionally, Cushing's syndrome occurs in otherwise healthy patients that have chronically elevated levels of cortisol - and these patients share many of the same symptoms as those with HD, including regional brain atrophy, cognitive decline, severe weight-loss and muscle wasting, osteoporosis and an increased likelihood of severe depression and anxiety. The goal of the studies proposed here are to first characterize the consequences of elevated corticosterone in the R6/2 transgenic mouse model of HD, and second to assess the role of mHTT pathology in the HPA-axis as a contributing factor to this neuroendocrine disturbance.
In Specific Aim 1, I will test the hypothesis that normalizing corticosterone levels in transgenic R6/2 mice will slow the onset and/or reduce the severity of cognitive (working and spatial memory), psychiatric (depression and anxiety-like behavior), metabolic (weight loss), and neuropathological symptoms (inclusion formation, gliosis, microglia activation).
In Specific Aim 2, I will test the hypothesis that mHTT expression in the hypothalamus and/or adrenal glands leads to hyperactivity of the HPA-axis, which in turn causes a rise in corticosterone shown by these mice. The ultimate goal of these studies is to determine whether or not the HPA-axis, and elevated cortisol/corticosterone is a suitable target for therapeutic intervention in the future.
HD is a fatal genetic neurological disorder that causes severe motor, cognitive, psychiatric, or metabolic symptoms, and there are no existing therapeutics that can slow disease progression. Symptomatic HD patients show significantly elevated levels of cortisol, and recent rodent studies indicate that elevated levels of corticosterone, the rodent homolog of cortisol, can exacerbate HD metabolic and cognitive symptoms and hasten time to death. The proposed work will test the hypothesis that normalizing corticosterone levels can reduce HD symptoms and slow the progression of the disease in a transgenic mouse model, and will also further characterize the contribution of mutant huntingtin toxicity in the HPA-axis t elevated corticosterone that is inherent to HD disease phenotype.
| Dufour, Brett D; McBride, Jodi L (2016) Corticosterone dysregulation exacerbates disease progression in the R6/2 transgenic mouse model of Huntington's disease. Exp Neurol 283:308-17 |
