Pla Patrick, Orvoen Sophie, Saudou Frédéric, David Denis J, Humbert Sandrine
Institut Curie Orsay, France ; CNRS UMR3306 Orsay, France ; INSERM U1005 Orsay, France ; Faculté des Sciences, Université Paris-Sud Orsay, France.
EA3544, Faculté de Pharmacie, Université Paris-Sud Châtenay-Malabry, France.
Front Behav Neurosci. 2014 Apr 23;8:135. doi: 10.3389/fnbeh.2014.00135. eCollection 2014.
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.
亨廷顿舞蹈症（HD）是一种神经退行性疾病，因其对运动控制的影响而最为人所知。抑郁、焦虑和易怒等情绪障碍在HD患者中也很常见，且往往在运动症状出现之前就已开始。HD的各种啮齿动物模型重现了患者中出现的焦虑/抑郁行为。HD是由一种名为亨廷顿蛋白（HTT）的350 kDa蛋白质N端的聚谷氨酰胺延伸片段扩增所致。HTT在全身广泛表达，并参与多种细胞功能，包括转录控制、囊泡运输、纤毛生成和有丝分裂。本综述总结了在理解HD患者行为障碍背后的细胞和分子机制方面所取得的进展。功能失调的HTT会影响与情绪障碍或对抗抑郁药反应相关的细胞通路，包括脑源性神经营养因子/酪氨酸激酶受体B（BDNF/TrkB）和血清素能信号传导。此外，HTT会影响成年海马神经发生，这是一种生理现象，与抗抑郁药的一些行为效应有关，并与焦虑控制有关。这些发现与野生型HTT作为神经元发育和生理的关键组成部分这一新兴作用相一致。因此，HTT中致病性的多聚谷氨酰胺扩增不仅可能通过获得新的毒性功能，还可能通过扰乱其正常功能而导致情绪障碍。
