AUG 30, 2016 08:00 AM PDT

Elucidating the physiological function of cellular PrPC using human iPS cel

  • Postdoctoral Fellow, University of Zurich, Switzerland
      Vijay Chandrasekar was born in the southern part of India called Tamil Nadu. He did his Master studies in microbial gene technology in Madurai Kamaraj University. Following that he worked as a research associate in the premier institute in India called India Institute of Science, where he worked on protein biochemistry and crystallography, where he was successfully involved in structure determination of several viral proteins. For his PhD, Vijay moved to Switzerland in 2010, where he did his doctoral studies in molecular neuroscience on "Characterization of microRNA and transcription factor gene network in cocaine induced neuroplasticity" in the University of Fribourg, Switzerland. His studies established the role of miRNAs in the addiction and neuronal plasticity induced by drugs of abuse in the brain for the very first time and resulted in several highly cited publications. After his PhD, Vijay moved to US to pursue his first postdoctoral fellowship at Columbia University Medical Center under the renowned scientist Prof. Tom Maniatis. during which time, he had his own Helmsley stem cell starter grant in CUMC for his studies on ALS disease using human iPS cells. Vijay worked on two interesting projects (a) HILO-RMCE based generation of iPS cells for studying C9orf72 mutation in ALS; (b) "Identifying the role of miRNAs in astrocyte dependent, non-cell autonomous motor neuron toxicity". He successfully initiated footprint-free reprogramming for in vitro disease modelling using iPS cells. Vijay is currently pursuing his second postdoctoral Scientist position in the Institute of Neuropathology, University Hospital Zurich, Switzerland, working under Prof. Adriano Aguzzi on "Establishing stem cell based systems ES and iPS cells for studying prion mutation in CJD". For the past almost 6 years, he has been working on mouse and human stem cells, both ES and iPS, to derive neurons and other cell lineages for disease modelling, characterization, and drug screening assays using variety of state-of-the-art methods like survival, morphometric measurements, RNAseq, and proteome analysis. Vijay has established the model systems in CUMC and in the University Hospital, Zurich as well as in our collaborative labs in Zurich.

    PrPC is a conserved lipid-raft associated, GPI-anchored cell membrane glycoprotein. Misfolding of cellular PrPC into the pathogenic PrPSc results in Prion disease, an untreatable and fatal neurodegenerative disorder. Prion induced neurotoxicity is preceded by impairment in metabolism of cholesterol and other lipids which are major component of lipid-rafts in affected neurons. Lipid-rafts deregulation has been implicated in diseases like Prion and AD, the mechanism remains unclear. Understanding the function of cellular PrPC may shed light on such pathological mechanisms. Towards this goal, we utilize a human induced pluripotent stem (iPS) cell model system. We generated isogenic PrP knockout (KO) human primary fibroblasts in order to reprogram them into PrP-KO-iPS cells and human neurons. Metabolomics and RNAseq analysis of these PrP-KO human cells show dysregulation in key CNS pathways like glycerophospholipid and cholesterol metabolism. Here we present a systems biological approach combining RNAseq and metabolomics to understand the functional molecular network of PrPC. The knowledge of key pathways in which PrPC  has important implications could aid in the targeted therapy for prion disorders

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