Why Woody got the blues: The neurobiology of depression in Huntington's disease

Abstract

Huntington's disease (HD) is an extraordinary disorder that usually strikes when individuals are in the prime of their lives, as was the case for the influential 20th century musician Woody Guthrie. HD demonstrates the exceptionally fine line between life and death in such 'genetic diseases', as the only difference between those who suffer horribly and die slowly of this disease is often just a handful of extra tandem repeats (beyond the normal polymorphic range) in a genome that constitutes over 3 billion paired nucleotides of DNA. Furthermore, HD presents as a complex and heterogenous combination of psychiatric, cognitive and motor symptoms, so can appear as an unholy trinity of 'three disorders in one'. The autosomal dominant nature of the disorder is also extremely challenging for affected families, as a 'flip of a coin' dictates which children inherit the mutation from their affected parent, and the gene-negative family members bear the burden of caring for the other half of the family that is affected. In this review, we will focus on one of the earliest, and most devastating, symptoms associated with HD, depression, which has been reported to affect approximately half of gene-positive HD family members. We will discuss the pathogenesis of HD, and depressive symptoms in particular, including molecular and cellular mechanisms, and potential genetic and environmental modifiers. This expanding understanding of HD pathogenesis may not only lead to novel therapeutic options for HD families, but may also provide insights into depression in the wider population, which has the greatest burden of disease of any disorder and an enormous unmet need for new therapies.

Keywords: Affective disorders; Depression; Huntington's disease; Mood disorders; Polyglutamine; Psychiatric disorders; Tandem repeat disorder; Tandem repeats.