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Cypermethrin Activates Autophagosome Formation Albeit Inhibits Autophagy Owing to Poor Lysosome Quality: Relevance to Parkinson’s Disease

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Abstract

Parkinson’s disease (PD) is the second most familiar, progressive and movement-related neurodegenerative disorder after Alzheimer disease. This study aimed to decipher the role of autophagy in cypermethrin-induced Parkinsonism, an animal model of PD. Indicators of autophagy [expression of beclin 1, autophagy-related protein 12 (Atg 12), unc-51 like autophagy activating kinase 1 (Ulk 1), p62 and lysosome-associated membrane protein 2 (LAMP 2) and conversion of microtubule-associated protein 1A/1B-light chain 3 (LC3) I to II], signalling cascade [phosphorylated (p) 5′ adenosine monophosphate-activated protein kinase (p-AMPK), sirtuin 1 (Sirt 1), phosphorylated-mammalian target of rapamycin (p-mTOR), tuberous sclerosis complex 2 (TSC 2), p317Ulk 1 and p757Ulk 1 levels] and lysosome morphology were assessed in control and cypermethrin-treated rat model of PD. Autophagy markers were also measured in cypermethrin-treated neuroblastoma cells in the presence of 3-methyl adenine, a phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) class III inhibitor; vinblastine, an autophagosome elongation inhibitor; bafilomycin A1, an autophagolysosome and lysosome fusion/abnormal acidification inhibitor or torin 1, a mechanistic target of rapamycin inhibitor. Cypermethrin reduced LAMP 2 and increased p-AMPK and Sirt 1 without causing any change in other signalling proteins. 3-Methyl adenine did not change LC3 conversion; vinblastine and bafilomycin A1 decreased LAMP 2 expression in controls. While cypermethrin increased LC3 conversion in the presence of 3-methyl adenine, LAMP 2 reduction was more pronounced in vinblastine and bafilomycin A1-treated cells. Torin 1 normalized the expression of LAMP 2 without any change in other autophagy markers. Results demonstrate that albeit cypermethrin activates autophagosome formation, it reduces LAMP 2 expression and lysosome quality leading to autophagy inhibition.

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Acknowledgements

The authors sincerely acknowledge the Council of Scientific and Industrial Research (CSIR), University Grants Commission and Department of Science and Technology India, respectively, for extending fellowship to Abhishek Kumar Mishra and Charul Rajput; Saumya Mishra and Mohd Sami ur Rasheed. The Science and Engineering Research Board (SERB), India (Project Reference No.: EMR/2016/005041), is gratefully appreciated for approving the study for financial support. CSIR-IITR communication number of this article is 3446.

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Authors and Affiliations

  1. Toxicogenomics and Predictive Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India

    Abhishek Kumar Mishra, Saumya Mishra, Charul Rajput, Mohd Sami ur Rasheed & Mahendra Pratap Singh

  2. Academy of Scientific and Innovative Research, CSIR-IITR Campus, Lucknow, 226001, Uttar Pradesh, India

    Abhishek Kumar Mishra, Saumya Mishra, Charul Rajput, Mohd Sami ur Rasheed, Devendra Kumar Patel & Mahendra Pratap Singh

  3. Analytical Chemistry Laboratory, Regulatory Toxicology Group, CSIR-IITR, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India

    Devendra Kumar Patel

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  1. Abhishek Kumar Mishra
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Correspondence to Mahendra Pratap Singh.

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Animal study was performed as per the guidelines of CPCSEA, India.

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IITR Communication Number: 3446

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Mishra, A.K., Mishra, S., Rajput, C. et al. Cypermethrin Activates Autophagosome Formation Albeit Inhibits Autophagy Owing to Poor Lysosome Quality: Relevance to Parkinson’s Disease. Neurotox Res 33, 377–387 (2018). https://doi.org/10.1007/s12640-017-9800-3

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  • DOI: https://doi.org/10.1007/s12640-017-9800-3

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