Laboratory of Functional Genomics and Molecular Toxicology, Division of Toxicology, CSIR-Central Drug Research Institute, Lucknow, India.
CNS Neurol Disord Drug Targets. 2012 Jun 1;11(4):387-94. doi: 10.2174/187152712800792811.
Neurodegenerative Parkinson's disease (PD) is a multifactorial disorder; effects like alpha synuclein aggregation, low dopamine levels and dopaminergic neurodegeneration are considered to be hallmarks of the disease. Several recent studies have pointed towards an important role of enzyme tyrosine hydroxylase (TH) in the pathophysiology of PD. We embarked on the present studies to explore the mechanistic role of C. elegans gene cat-2, a putative tyrosine hydroxylase, in PD. Utilizing the powerful genetic model system C. elegans, which has previously provided critical understanding of several human diseases, we employed a reverse genetics approach via RNAi mediated gene silencing of cat-2, to study various disease related effects in three different transgenic strains of the nematode. Knocking-down of cat-2 led to increase in aggregation of alpha synuclein, as was studied via expression of YFP. Similarly the silencing of cat-2 had significant effects on associated endpoints including oxidative stress, lipid content and neurotransmission; exemplifying the role of cat-2, the putative tyrosine hydroxylase, in Parkinsonism of the nematode model. The findings are significant as this model could further be used to study the entire associated pathway in greater detail and with the advantages that the model system C. elegans presents, the knockdown of cat-2 in the alpha synuclein expressing strain, could be employed for screening potential pharmacological agents targeted at TH which could lead to designing of possible therapeutic interventions for the disease.
神经退行性帕金森病（PD）是一种多因素疾病；α-突触核蛋白聚集、多巴胺水平降低和多巴胺能神经退行性变等效应被认为是该疾病的标志。最近的几项研究表明，酶酪氨酸羟化酶（TH）在 PD 的病理生理学中起着重要作用。我们着手进行本研究，以探索秀丽隐杆线虫基因 cat-2（假定的酪氨酸羟化酶）在 PD 中的机制作用。利用强大的遗传模型系统秀丽隐杆线虫，该系统先前为几种人类疾病提供了关键的理解，我们通过 RNAi 介导的 cat-2 基因沉默，采用反向遗传学方法，在三种不同的线虫转基因株系中研究了与疾病相关的各种效应。cat-2 的敲低导致α-突触核蛋白聚集增加，这是通过 YFP 的表达来研究的。同样，cat-2 的沉默对相关终点也有显著影响，包括氧化应激、脂质含量和神经传递；作为假定的酪氨酸羟化酶的 cat-2 的作用例证，该基因在线虫模型的帕金森病中发挥作用。这些发现意义重大，因为该模型可以进一步用于更详细地研究整个相关途径，并且由于秀丽隐杆线虫模型系统具有优势，因此可以在表达α-突触核蛋白的线虫株系中敲低 cat-2，用于筛选针对 TH 的潜在药物，从而为该疾病设计可能的治疗干预措施。
