Cha J H, Frey A S, Alsdorf S A, Kerner J A, Kosinski C M, Mangiarini L, Penney J B, Davies S W, Bates G P, Young A B
Department of Neurology, Massachusetts General Hospital, Boston 02114, USA.
Philos Trans R Soc Lond B Biol Sci. 1999 Jun 29;354(1386):981-9. doi: 10.1098/rstb.1999.0449.
Alterations in neurotransmitter receptors are a pathological hallmark of the neurodegeneration seen in Huntington's disease (HD). However, the significance of these alterations has been uncertain, possibly reflecting simply the loss of brain cells. It is not known for certain whether the alteration of neurotransmitter receptors occurs before the onset of symptoms in human HD. Recently we developed transgenic mice that contain a portion of a human HD gene and develop a progressive abnormal neurological phenotype. Neurotransmitter receptors that are altered in HD (receptors for glutamate, dopamine, acetylcholine and adenosine) are decreased in the brain transgenic mice, in some cases before the onset of behavioural or motor symptoms. In transgenic mice, neurotransmitter receptor alterations occur before neuronal death. Further, receptor alterations are selective in that certain receptors, namely N-methyl-D-aspartate and gamma-aminobutyric acid receptors, are unaltered. Finally, receptor decreases are preceded by selective decreases in the corresponding mRNA species, suggesting the altered transcription of specific genes. These results suggest that (i) receptor decreases precede, and therefore might contribute to, the development of clinical symptoms, and (ii) altered transcription of specific genes might be a key pathological mechanism in HD.
神经递质受体的改变是亨廷顿舞蹈病（HD）中神经退行性变的一个病理标志。然而，这些改变的意义尚不确定，可能仅仅反映了脑细胞的丧失。目前尚不清楚在人类HD中神经递质受体的改变是否在症状出现之前就已发生。最近，我们培育出了含有部分人类HD基因并表现出进行性异常神经表型的转基因小鼠。在HD中发生改变的神经递质受体（谷氨酸、多巴胺、乙酰胆碱和腺苷的受体）在转基因小鼠脑中减少，在某些情况下是在行为或运动症状出现之前。在转基因小鼠中，神经递质受体的改变发生在神经元死亡之前。此外，受体改变具有选择性，即某些受体，即N-甲基-D-天冬氨酸和γ-氨基丁酸受体未发生改变。最后，在受体减少之前，相应的mRNA种类会选择性减少，这表明特定基因的转录发生了改变。这些结果表明：（i）受体减少先于临床症状的出现，因此可能促成了临床症状的发展；（ii）特定基因转录的改变可能是HD的关键病理机制。
