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Metabolomic Analysis Provides Insights on Paraquat-Induced Parkinson-Like Symptoms in Drosophila melanogaster

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Abstract

Paraquat (PQ) exposure causes degeneration of the dopaminergic neurons in an exposed organism while altered metabolism has a role in various neurodegenerative disorders. Therefore, the study presented here was conceived to depict the role of altered metabolism in PQ-induced Parkinson-like symptoms and to explore Drosophila as a potential model organism for such studies. Metabolic profile was generated in control and in flies that were fed PQ (5, 10, and 20 mM) in the diet for 12 and 24 h concurrent with assessment of indices of oxidative stress, dopaminergic neurodegeneration, and behavioral alteration. PQ was found to significantly alter 24 metabolites belonging to different biological pathways along with significant alterations in the above indices. In addition, PQ attenuated brain dopamine content in the exposed organism. The study demonstrates that PQ-induced alteration in the metabolites leads to oxidative stress and neurodegeneration in the exposed organism along with movement disorder, a phenotype typical of Parkinson-like symptoms. The study is relevant in the context of Drosophila and humans because similar alteration in the metabolic pathways has been observed in both PQ-exposed Drosophila and in postmortem samples of patients with Parkinsonism. Furthermore, this study provides advocacy towards the applicability of Drosophila as an alternate model organism for pre-screening of environmental chemicals for their neurodegenerative potential with altered metabolism.

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Acknowledgments

The authors are thankful to the Director, Dr. C. S. Nautiyal for support. We thank Bloomington Stock Centre, USA, for Oregon R + fly stock and Dr. Wendi Neckameyer, MO, USA, for anti-Drosophila Tyrosine Hydroxylase antibody, and Mr. Ram Narayan, Technical Officer, CSIR-IITR, Lucknow, for his help in confocal microscopy. Financial support to AKS (Grant No. EU249IV/2008/JUNE/318721) from the University Grants Commission (UGC), New Delhi, and to ChR (Grant No.20-6/2008(ii)/EU-IV), to PP (Grant No. 31/029(0199)/2008-EMR-1), and HSC (Grant No. 19-06/2011(i)/EU-IV) from the Council of Scientific and Industrial Research (CSIR), New Delhi, MKRM from CSIR-Network project (BSC0111), and to DKC from CSIR-Network project (BSC-0103) is thankfully acknowledged. IITR communication number is 3262.

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The authors declare that there is no conflict of interest.

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Authors and Affiliations

  1. Embryotoxicology Section, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India

    Arvind Kumar Shukla, Prakash Pragya, Hitesh Singh Chaouhan & Debapratim Kar Chowdhuri

  2. Analytical Chemistry Section, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India

    Ch. Ratnasekhar, Devendra Kumar Patel & Mohana Krishna Reddy Mudiam

  3. Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR Campus, Lucknow, India

    Ch. Ratnasekhar, Hitesh Singh Chaouhan, Devendra Kumar Patel, Debapratim Kar Chowdhuri & Mohana Krishna Reddy Mudiam

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  1. Arvind Kumar Shukla
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Correspondence to Debapratim Kar Chowdhuri or Mohana Krishna Reddy Mudiam.

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The authors Arvind Kumar Shukla, Ch. Ratnasekhar, and Prakash Pragya contributed equally.

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Table S1

(DOC 48 kb)

Fig S1

Partial least-square discriminate analysis (PLS-DA) of metabolome from adult Drosophila brain showing control-12 and 24 h (1–2), 5, 10, and 20 mM PQ for 12 h (3–5) and 24 h (6–8) respectively (GIF 15 kb)

High-resolution image (TIFF 1686 kb)

Fig S2

Permutation analysis of PLS-DA models derived from control and PQ-exposed Drosophila brain samples. Statistical validation of the PLS-DA was done by permutation analysis using 500 different model permutations. The goodness of fit and predictive capability of the original class assignments are much higher compared with ratios based on the permutation class assignments (GIF 3 kb)

High-resolution image (TIFF 706 kb)

Fig S3

Individual PCA scores plots of PC1 (first PCA component) versus PC2 (second PCA component) for GC-MS spectra of the brain tissue samples of D. melanogaster showing separation profile of control flies from PQ-exposed organism under different treatment conditions; 5, 10, and 20 mM PQ for 12 h versus control-12 h (a–c), and the same PQ exposure concentrations for 24 h versus control-24 h (d–f) respectively (GIF 32 kb)

High-resolution image (TIFF 4085 kb)

Fig S4

Individual PCA scores plots of PC1 (first PCA component) versus PC2 (second PCA component) for GC-MS spectra of the brain tissue extracts of D. melanogaster after 12 h (a) and 24 h (b) of PQ exposure to fly; control-12 and control-24 h (1–2), 5, 10, and 20 mM PQ for 12 h (3–5) and 24 h (6–8) respectively (GIF 11 kb)

High-resolution image (TIFF 1523 kb)

Fig S5

Predictive accuracy of the model discriminating brain samples of control from that of PQ-exposed Drosophila using ROC curve analysis (GIF 6 kb)

High-resolution image (TIFF 966 kb)

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Shukla, A.K., Ratnasekhar, C., Pragya, P. et al. Metabolomic Analysis Provides Insights on Paraquat-Induced Parkinson-Like Symptoms in Drosophila melanogaster . Mol Neurobiol 53, 254–269 (2016). https://doi.org/10.1007/s12035-014-9003-3

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