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Dopamine promotes cathepsin B-mediated amyloid precursor protein degradation by reactive oxygen species-sensitive mechanism in neuronal cell

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Abstract

Recent literature suggested an important function of native amyloid precursor protein (APP) as amine oxidase implicating in protection of brain cells from catecholamine-induced toxicity. However, any role of catecholamines on regulation of native APP has not been explored. Here we report that dopamine (DA), one of the most prominent catecholamine neurotransmitters in brain, down-modulates native APP protein in several neuronal cell types. Using SH-SY5Y cells as model, we detected no alteration of transcript expression and unaffected translation suggested that DA might induce APP degradation. We actually found that DA treatment decreased the stability of APP. Lysosomal blockers inhibited DA-induced APP degradation, but specific proteasomal blocker failed to do so. We detected the role of cathepsin B in DA-induced APP degradation by using pharmacological inhibitor and specific siRNA. We also revealed that DA could increase cathepsin B expression at both transcript and protein levels. Using antioxidant N-acetyl cysteine, we detected increased level of reactive oxygen species generation that was found responsible for induced cathepsin B expression by DA and resultant APP degradation. Our study reveals the existence of reciprocal regulation of a catecholamine and an amine oxidase implicating in brain catecholamine homeostasis.

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Acknowledgements

CKM acknowledges financial support received from Department of Biotechnology, India, and the National Initiative on Glial Cell Research in Health and Disease from Department of Biotechnology; Indian Council of Medical Research-CAR grant to SCMM; University with potential for excellence (UPE-II) to JNU and Department of Science and Technology-PURSE program to Jawaharlal Nehru University. SK was supported by fellowship from Department of Biotechnology, India; AM thanks DS Kothari postdoctoral fellowship from UGC.

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  1. Sanju Kumari

    Present address: National Institute of Malaria Research, New Delhi, India

Authors and Affiliations

  1. Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India

    Sanju Kumari, Abhishek Mukherjee & Chinmay K. Mukhopadhyay

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  1. Sanju Kumari
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  2. Abhishek Mukherjee
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CKM conceived, designed, analyzed and coordinated the study and wrote the paper. SK conceived, designed, performed, analyzed experiments and wrote the paper. AM designed and performed experiments. All authors reviewed the results and approved the final version of the manuscript.

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Correspondence to Chinmay K. Mukhopadhyay.

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Kumari, S., Mukherjee, A. & Mukhopadhyay, C.K. Dopamine promotes cathepsin B-mediated amyloid precursor protein degradation by reactive oxygen species-sensitive mechanism in neuronal cell. Mol Cell Biochem 454, 153–163 (2019). https://doi.org/10.1007/s11010-018-3460-3

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