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A Systematic RNAi Screen of Neuroprotective Genes Identifies Novel Modulators of Alpha-Synuclein-Associated Effects in Transgenic Caenorhabditis elegans

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Abstract

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder, defined clinically by degeneration of dopaminergic neurons and the development of neuronal Lewy bodies. Current treatments of PD are inadequate due to a limited understanding of molecular events of the disease, thus calling for intense research efforts towards identification of novel therapeutic targets. We carried out the present studies towards identifying novel genetic modulators of PD-associated effects employing a transgenic Caenorhabditis elegans model expressing human alpha-synuclein. Employing a systematic RNA interference (RNAi)-based screening approach, we studied a set of neuroprotective genes of C. elegans with an aim of identifying genes that exhibit protective function under alpha-synuclein expression conditions. Our results reveal a novel set of alpha-synuclein effector genes that modulate alpha-synuclein aggregation and associated effects. The identified genes include those from various gene families including histone demethylase, lactate dehydrogenase, small ribosomal subunit SA protein, cytoskeletal protein, collapsin response mediator protein, and choline kinase. The functional characterization of these genes reveals involvement of signaling mechanisms such as Daf-16 and acetylcholine signaling. Further elucidation of mechanistic pathways associated with these genes will yield additional insights into mediators of alpha-synuclein-induced cytotoxicity and cell death, thereby helping in the identification of potential therapeutic targets for PD.

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Acknowledgments

C. elegans strains were obtained from the Caenorhabditis Genetics Center (CGC) University of Minnesota, MN, USA, which is funded by the NIH National Center for Research Resources (NCRR). The confocal microscopy facility of CSIR-CDRI is acknowledged for making the facility available to us; Dr. Kavita Singh is gratefully acknowledged for her help with imaging. A. N. acknowledges the financial support received from CSIR-NWP “UNDO” (BSC0103). P. J. is thankful to CSIR for the Senior Research Fellowship (Ref: 113558/2 K11/1). CSIR-CDRI communication number is 9114.

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Authors and Affiliations

  1. Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2 Rafi Marg, New Delhi, 110 001, India

    Pooja Jadiya & Aamir Nazir

  2. Laboratory of Functional Genomics and Molecular Toxicology, Division of Toxicology, CSIR—Central Drug Research Institute, Lucknow, 226 031, India

    Pooja Jadiya, Soobiya Fatima, Tanvi Baghel & Aamir Nazir

  3. Department of Bioengineering, Integral University, Kursi Road, Lucknow, 226 026, India

    Soobiya Fatima & Snober S. Mir

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  1. Pooja Jadiya
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Correspondence to Aamir Nazir.

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Jadiya, P., Fatima, S., Baghel, T. et al. A Systematic RNAi Screen of Neuroprotective Genes Identifies Novel Modulators of Alpha-Synuclein-Associated Effects in Transgenic Caenorhabditis elegans . Mol Neurobiol 53, 6288–6300 (2016). https://doi.org/10.1007/s12035-015-9517-3

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  • DOI: https://doi.org/10.1007/s12035-015-9517-3

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