Translational Neuroendocrinology

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Prevention of depressive behaviour in the YAC128 mouse model of Huntington disease by mutation at residue 586 of huntingtin

Pouladi M, Graham RK, Karasinska JM, Xie Y, Dar Santos R, Petersén Å, and Hayden MR

1 Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, V6T 1Z3 Canada 2 Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Vancouver, British Columbia, V5Z 4H4 Canada 3 Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, 221 84 Sweden

Brain 132 (4): 919-932 (2009)

 Abstract 

Huntington disease is a neurodegenerative disorder caused by an expanded CAG repeat in the Huntington disease gene. The symptomatic phase of the disease is defined by the onset of motor symptoms. However, psychiatric disturbances, including depression, are common features of Huntington disease and recent studies indicate that depression can occur long before the manifestation of motor symptoms. The aetiology of depression in Huntington disease is not fully understood and psychosocial factors such as the knowledge of carrying a mutation for an incurable disease or adverse social circumstances may contribute to its presentation. Due to the difficulties in discriminating between social and biological factors as contributors to depression in clinical Huntington disease, we chose to assess whether a model for Huntington disease not subject to environmental stressors, namely the YAC mouse model of Huntington disease, displays a depressive phenotype. Indeed, the YAC transgenic mice recapitulate the early depressive phenotype of Huntington disease as assessed by the Porsolt forced swim test as well as the sucrose intake test as a measure of anhedonia. The YAC model mirrors clinical Huntington disease in that there were no effects of CAG repeat length or disease duration on the depressive phenotype. The depressive phenotype was completely rescued in YAC transgenic animals expressing a variant of mutant huntingtin that is resistant to cleavage at amino acid 586 suggesting that therapies aimed towards inhibition of huntingtin cleavage are also likely to have beneficial effects on this aspect of the disease. In conclusion, our study provides strong support for a primary neurobiological basis for depression in Huntington disease.

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