Chapter 20 - Stress and Glucocorticoids as Experience-Dependent Modulators of Huntington's Disease

Abstract

Huntington's disease (HD) is a neurodegenerative disorder largely governed by genetics. The cause of this tandem repeat disorder is a fully penetrant trinucleotide (CAG), inherited via autosomal dominant transmission. The length of this expanded tandem repeat in HD also predicts the age of disease onset, which can range from early childhood to late adulthood. Previous research utilizing transgenic HD mice demonstrated that environmental factors can alter symptom progression. Environmental enrichment and voluntary wheel running delayed or ameliorated the triad of motor, affective, and cognitive dysfunctions in HD mice. Recent clinical studies also suggest that lifestyle factors can affect the age of onset. Currently, there are no treatments to slow or change the course of HD so environmental interventions may offer a feasible approach to extend the symptom-free years in HD gene-positive individuals. There is evidence to suggest that the stress response is abnormal in HD mice and patients. The present article reviews the evidence addressing the impact of stressors on the onset and progression in HD mice. Our research using acute and chronic stress paradigms demonstrated the negative impact on endophenotypes modeling symptoms of HD. The stress interventions were able to modulate pathogenesis in a transgenic mouse model of HD, notably, accelerating cognitive decline and other endophenotypes. This research demonstrates that stress is not only able to accelerate onset of specific deficits in HD mice, but also suggests that the gene mutation may confer a susceptibility to the negative effects of stress. These findings have implications for the development of novel approaches to delay onset and slow progression of this devastating tandem repeat disorder. One implication is that behavioral management therapy in combination with other lifestyle changes may help delay onset, and slow progression of the disease, in gene-positive individuals. Further research into mechanisms mediating environmentally modulated pathogenic processes will also identify molecular targets for novel therapeutics, such as enviromimetics.