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Title: Prostaglandin A2 interacts with Nurr1 and ameliorates behavioral deficits in Parkinson's disease fly model
Authors: Rajan, Sreekanth
Toh, Hui Ting
Ye, Hong
Wang, Ziyin
Basil, Adeline Henry
Parnaik, Tanvi
Yoo, Jun Yeob
Lim, Kah-Leong
Yoon, Ho Sup
Keywords: Science::Medicine
Issue Date: 2022
Source: Rajan, S., Toh, H. T., Ye, H., Wang, Z., Basil, A. H., Parnaik, T., Yoo, J. Y., Lim, K. & Yoon, H. S. (2022). Prostaglandin A2 interacts with Nurr1 and ameliorates behavioral deficits in Parkinson's disease fly model. Neuromolecular Medicine.
Project: MOE2016-T2-2-055
Journal: Neuromolecular Medicine
Abstract: The orphan nuclear receptor Nurr1 is critical for the development, maintenance, and protection of midbrain dopaminergic neurons. Recently, we demonstrated that prostaglandins E1 (PGE1) and PGA1 directly bind to the ligand-binding domain (LBD) of Nurr1 and stimulate its transcriptional activation function. In this direction, here we report the transcriptional activation of Nurr1 by PGA2, a dehydrated metabolite of PGE2, through physical binding ably supported by NMR titration and crystal structure. The co-crystal structure of Nurr1-LBD bound to PGA2 revealed the covalent coupling of PGA2 with Nurr1-LBD through Cys566. PGA2 binding also induces a 21° shift of the activation function 2 (AF-2) helix H12 away from the protein core, similar to that observed in the Nurr1-LBD-PGA1 complex. We also show that PGA2 can rescue the locomotor deficits and neuronal degeneration in LRRK2 G2019S transgenic fly models.
ISSN: 1535-1084
DOI: 10.1007/s12017-022-08712-3
Rights: © 2022 The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. All rights reserved.
Fulltext Permission: none
Fulltext Availability: No Fulltext
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