Differential regulation of human tyrosine hydroxylase isoforms and the development of Parkinson's disease

帕金森氏症是一种常见的神经退行性疾病，其主要特征是大脑黑质中含有多巴胺的神经缺失。黑质内神经的损失并不均匀，但首先并主要影响腹侧细胞，这表明特定的多巴胺能神经元更容易受到疾病过程的影响。理解帕金森氏症的关键在于弄清楚为什么这些细胞比大脑中的其他多巴胺能细胞更容易退化。酪氨酸羟化酶控制多巴胺合成的速率。人类的独特之处在于他们含有四种酪氨酸羟化酶的异构体，因此他们有可能以其他物种没有的方式改变多巴胺合成的调节。我们实验室的最新进展表明，酪氨酸羟化酶的特定异构体可能在帕金森病中多巴胺能神经元对变性的易感性中起作用，或者在疾病症状的时间中起作用。我们已经证明了人类TH亚型在黑质内分布的差异，某些亚型在易感的腹侧细胞中更为普遍。我们还表明，在四种人类酪氨酸羟化酶异构体的调节中存在主要差异。一些同工异构体对神经元的高频刺激更敏感，而另一些对低频持续刺激更敏感。这将提供一种机制，通过这种机制，人类TH亚型的不同分布将导致人类大脑不同部位多巴胺合成的改变，这可能反过来导致对帕金森病的易感性增加或症状的早期出现。

Parkinson's disease is a common neurodegenerative disease whose major feature is loss of a dopamine containing nerves in a part of the brain called the substantia nigra. Loss of nerves within the substantia nigra is not uniform, but firstly and primarily affects the ventral cells, suggesting that particular dopaminergic neurons are more vulnerable to the disease process. A key to understanding Parkinson's disease would be to work out why these cells are more susceptible to degeneration than other dopaminergic cells in the brain. Tyrosine hydroxylase controls the rate of dopamine synthesis. Humans are unique in that they contain four isoforms of tyrosine hydroxylase and therefore they have the potential to alter the regulation of dopamine synthesis in ways that other species do not. Recent developments in our laboratories have suggested that particular isoforms of tyrosine hydroxylase may have either a role in the susceptibility of dopaminergic neurons to degeneration in Parkinson's disease or a role in the timing of the symptoms of the disease. We have demonstrated differences in the distribution of the human TH isoforms within the substantia nigra, with certain isoforms being more prevalent in the susceptible ventral cells. We have also shown that there are major differences in the regulation of the four human tyrosine hydroxylase isoforms. Some isoforms will be more sensitive to conditions that occur with high frequency stimulation of neurons and some to low frequency sustained stimulation. This would provide a mechanism by which differential distribution of the human TH isoforms would result in altered dopamine synthesis in different parts of the human brain and this may in turn lead to either increased susceptibility to, or earlier appearance of symptoms of, Parkinson's disease.