Tryptophan hydroxylase 2 aggregates through disulfide cross-linking upon oxidation: possible link to serotonin deficits and non-motor symptoms in Parkinson's disease.
Tryptophan hydroxylase 2 aggregates through disulfide cross-linking upon oxidation: possible link to serotonin deficits and non-motor symptoms in Parkinson's disease.
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DOI：
10.1111/j.1471-4159.2010.07123.x
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发表时间：
2011-02
影响因子：
4.7
通讯作者：
Bishop C
中科院分区：
文献类型：
--
作者：
Kuhn DM;Sykes CE;Geddes TJ;Jaunarajs KL;Bishop C
帕金森病（PD）是一种进行性神经退行性疾病，其特征是黑质纹状体系统的多巴胺神经元丢失，导致严重的运动障碍。虽然不太受重视，但非运动症状在PD中也很常见，许多可以追溯到5-羟色胺神经元缺陷。色氨酸羟化酶2（TPH 2）是5-羟色胺生物合成中的限速酶，是5-羟色胺神经元的表型标志物，已知其对氧化极不稳定。因此，PD中普遍存在的氧化过程可能导致TPH 2错误折叠并改变5 HT神经元功能，就像在多巴胺神经元中所看到的那样。TPH 2的氧化抑制酶活性，并导致以二硫苏糖醇可逆方式形成高分子量聚集体。半胱氨酸扫描诱变显示，只要单个半胱氨酸残基（每个单体总共13个）保留在TPH 2中，它就会在氧化后交联，只有半胱氨酸较少的突变体才能抵抗这种效应。氧化剂对TPH 2催化功能和交联的影响也在完整的TPH 2表达HEK 293细胞中观察到。氧化将TPH 2从可溶性隔室转移到膜组分和大的包涵体中。连续非还原/还原二维SDS-PAGE和免疫印迹证实，TPH 2是少数形成二硫键结合的聚集体的胞质蛋白之一。TPH 2在其半胱氨酸残基氧化后错误折叠的倾向是其催化不稳定性的原因，并且可能与PD中5-羟色胺神经元功能的丧失和非运动（精神）症状的出现有关。
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopamine neurons of the nigrostriatal system, resulting in severe motor disturbances. Although much less appreciated, non-motor symptoms are also very common in PD and many can be traced to serotonin neuronal deficits. Tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme in the serotonin biosynthesis, is a phenotypic marker for serotonin neurons and is known to be extremely labile to oxidation. Therefore, the oxidative processes that prevail in PD could cause TPH2 misfolding and modify 5HT neuronal function much as is seen in dopamine neurons. Oxidation of TPH2 inhibits enzyme activity and leads to the formation of high molecular weight aggregates in a dithiothreitol-reversible manner. Cysteine-scanning mutagenesis shows that as long as a single cysteine residue (out of a total of 13 per monomer) remains in TPH2, it cross-links upon oxidation and only cysteine-less mutants are resistant to this effect. The effects of oxidants on TPH2 catalytic function and cross-linking are also observed in intact TPH2-expressing HEK293 cells. Oxidation shifts TPH2 from the soluble compartment into membrane fractions and large inclusion bodies. Sequential non-reducing/reducing two-dimensional SDS-PAGE and immunoblotting confirmed that TPH2 was one of a small number of cytosolic proteins that form disulfide-bonded aggregates. The propensity of TPH2 to misfold upon oxidation of its cysteine residues is responsible for its catalytic lability and may be related to loss of serotonin neuronal function in PD and the emergence of non-motor (psychiatric) symptoms.
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
2.9
作者：
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通讯作者：
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影响因子：
11.2
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
11
作者：
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通讯作者：
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