Mood disorders in Huntington's disease: from behavior to cellular and molecular mechanisms

Abstract

Huntington's disease (HD) is a neurodegenerative disorder that is best known for its effect on motor control. Mood disturbances such as depression, anxiety, and irritability also have a high prevalence in patients with HD, and often start before the onset of motor symptoms. Various rodent models of HD recapitulate the anxiety/depressive behavior seen in patients. HD is caused by an expanded polyglutamine stretch in the N-terminal part of a 350 kDa protein called huntingtin (HTT). HTT is ubiquitously expressed and is implicated in several cellular functions including control of transcription, vesicular trafficking, ciliogenesis, and mitosis. This review summarizes progress in efforts to understand the cellular and molecular mechanisms underlying behavioral disorders in patients with HD. Dysfunctional HTT affects cellular pathways that are involved in mood disorders or in the response to antidepressants, including BDNF/TrkB and serotonergic signaling. Moreover, HTT affects adult hippocampal neurogenesis, a physiological phenomenon that is implicated in some of the behavioral effects of antidepressants and is linked to the control of anxiety. These findings are consistent with the emerging role of wild-type HTT as a crucial component of neuronal development and physiology. Thus, the pathogenic polyQ expansion in HTT could lead to mood disorders not only by the gain of a new toxic function but also by the perturbation of its normal function.

Disease stage, but not sex, predicts depression and psychological distress in Huntington's disease: A European population study

“…The current findings of no observed sex differences in distress is also inconsistent with the trend for sexual dimorphism found in mice models with HD [19]. One body of research has identified depression to be associated with altered hypothalamic-pituitary-19 adrenal (HPA)-axis functioning (44)(45)(46)(47), and these mechanisms have been proposed for sex differences in depressive behaviours in rodents [48].…”

“…Of the limited human studies available, there is evidence to suggest that the usual ratio of discrepancy noted between men and women does not exist in HD [9,18]. More research regarding sex differences in anxiety and depressive-like behaviours in HD has been undertaken using various mice models [19]. Animal models of HD enable researchers to consider the aetiology of behavioural symptoms and also mechanisms underlying sex differences, as potential biological contributions can be tested in the absence 6 of psychosocial issues affecting human gene carriers, such as the knowledge that they have a fatal neurodegenerative condition.…”

“…In these tests, female mice have been shown to demonstrate more behaviours suggestive of depression [22][23][24]. Therefore, collectively, there is evidence of sexual dimorphism of anxiety and depressive-like behaviours in rodent models of HD, with suggestion of a potential interaction between sex differences and stage of disease progression [19], an area that has not been examined in humans.…”

Depression and clinical progression in spinocerebellar ataxias

“…Depression is a common comorbidity in neurodegenerative disorders, such as Parkinson’s disease (PD) [10] and Huntington’s disease (HD) [11], and is thought to arise from neurodegeneration in the depression-related brain circuitry in these disorders. Depressive symptoms could even precede the motor impairment in PD and HD, arguing against that depression merely results from motor disability.…”

Neurochemical correlation between major depressive disorder and neurodegenerative diseases

“…Several studies have shown a strong association between MDD and HD [93]. In addition, the incidence of suicide is higher in patients with HD than the general population; this association has been attributed to physiological degeneration [94].…”