title: RNAi of cat-2, a putative tyrosine hydroxylase, increases alpha synuclein aggregation and associated effects in transgenic C. elegans.
abstract: 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.
authors.affiliation: Laboratory of Functional Genomics and Molecular Toxicology, Division of Toxicology, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Supinder
authors.initials: S
authors.lastname: Kaur
authors.forename: Shreesh Raj
authors.initials: SR
authors.lastname: Sammi
authors.forename: Pooja
authors.initials: P
authors.lastname: Jadiya
authors.forename: Aamir
authors.initials: A
authors.lastname: Nazir
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D006899:Mixed Function Oxygenases / Q000235:genetics*; D034622:RNA Interference / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis* / Q000235:genetics; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D051844:alpha-Synuclein; C088760:cat-2 protein, C elegans; D006899:Mixed Function Oxygenases; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine