Pouladi Mahmoud A, Graham Rona K, Karasinska Joanna M, Xie Yuanyun, Santos Rachelle Dar, Petersén Asa, Hayden Michael R
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, V6T 1Z3 Canada.
Brain. 2009 Apr;132(Pt 4):919-32. doi: 10.1093/brain/awp006. Epub 2009 Feb 18.
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.
亨廷顿舞蹈症是一种神经退行性疾病，由亨廷顿舞蹈症基因中的CAG重复序列扩增引起。该疾病的症状期由运动症状的出现来定义。然而，包括抑郁症在内的精神障碍是亨廷顿舞蹈症的常见特征，最近的研究表明，抑郁症可能在运动症状出现之前很久就会发生。亨廷顿舞蹈症中抑郁症的病因尚未完全明确，心理社会因素，如知晓携带不治之症的突变或不利的社会环境，可能导致其出现。由于在临床亨廷顿舞蹈症中难以区分导致抑郁症的社会因素和生物学因素，我们选择评估一种不受环境应激源影响的亨廷顿舞蹈症模型，即亨廷顿舞蹈症的酵母人工染色体（YAC）小鼠模型，是否表现出抑郁表型。事实上，通过波索尔特强迫游泳试验以及作为快感缺失指标的蔗糖摄取试验评估，YAC转基因小鼠重现了亨廷顿舞蹈症早期的抑郁表型。YAC模型反映了临床亨廷顿舞蹈症的情况，即CAG重复序列长度或病程对抑郁表型没有影响。在表达对586位氨基酸切割具有抗性的突变亨廷顿蛋白变体的YAC转基因动物中，抑郁表型完全得到挽救，这表明旨在抑制亨廷顿蛋白切割的疗法也可能对该疾病的这一方面产生有益影响。总之，我们的研究为亨廷顿舞蹈症中抑郁症的原发性神经生物学基础提供了有力支持。
