Abstract
Huntington’s disease (HD) is an autosomal dominant disorder caused by a tandem repeat expansion encoding an expanded tract of glutamines in the huntingtin protein. HD is progressive and manifests as psychiatric symptoms (including depression), cognitive deficits (culminating in dementia), and motor abnormalities (including chorea). Having reached the twentieth anniversary of the discovery of the “genetic stutter” which causes HD, we still lack sophisticated insight into why so many HD patients exhibit affective disorders such as depression at very early stages, prior to overt appearance of motor deficits. In this review, we will focus on depression as the major psychiatric manifestation of HD, discuss potential mechanisms of pathogenesis identified from animal models, and compare depression in HD patients with that of the wider gene-negative population. The discovery of depressive-like behaviors as well as cellular and molecular correlates of depression in transgenic HD mice has added strong support to the hypothesis that the HD mutation adds significantly to the genetic load for depression. A key question is whether HD-associated depression differs from that in the general population. Whilst preclinical studies, clinical data, and treatment responses suggest striking similarities, there are also some apparent differences. We discuss various molecular and cellular mechanisms which may contribute to depression in HD, and whether they may generalize to other depressive disorders. The autosomal dominant nature of HD and the existence of models with excellent construct validity provide a unique opportunity to understand the pathogenesis of depression and associated gene-environment interactions. Thus, understanding the pathogenesis of depression in HD may not only facilitate tailored therapeutic approaches for HD sufferers, but may also translate to the clinical depression which devastates the lives of so many people.
Highlights
Huntington’s disease (HD) is a progressive neurodegenerative disorder that affects mood, cognition, and movement
Depression is notoriously heterogeneous in its presentation and these findings suggest possible dominance of a different cluster of symptoms in HD compared to most clinical depression patients
HD is disrupted, due to sequestration of its binding partner, cAMP response element-binding protein (CREB) binding protein (CBP). This is a common molecular pathology that the disease shares with depression, and one which, along with the target gene BDNF as described below, is likely to mediate the deficits in hippocampal neurogenesis which is the cellular consistently observed in animal models of HD
Summary
Huntington’s disease (HD) is a progressive neurodegenerative disorder that affects mood, cognition, and movement. We will focus on depression as the major psychiatric manifestation of HD, discuss potential mechanisms of pathogenesis identified from animal models, and compare depression in HD patients with that of the wider gene-negative population.
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