Prostaglandin A2 Interacts with Nurr1 and Ameliorates Behavioral Deficits in Parkinson’s Disease Fly Model

• Published in: Neuromolecular medicine Vol. 24; no. 4; pp. 469 - 478
• Main Authors: Rajan, Sreekanth, Toh, Hui Ting, Ye, Hong, Wang, Ziyin, Basil, Adeline Henry, Parnaik, Tanvi, Yoo, Jun Yeob, Lim, Kah-Leong, Yoon, Ho Sup
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.12.2022; Springer Nature B.V
• Subjects: Biomedical and Life Sciences; Biomedicine; Crystal structure; Degeneration; Dopamine; Dopamine receptors; Internal Medicine; Kinases; Ligands; LRRK2 protein; Medicine; Mesencephalon; Movement disorders; Neurodegeneration; Neurodegenerative diseases; Neurology; Neurosciences; NMR; Nuclear magnetic resonance; Nuclear receptors; Nurr1 protein; Original Paper; Parkinson's disease; Plasmids; Prostaglandin E2; Prostaglandins; Proteins; Titration; Transcription activation; NR4A2; Nuclear receptor; Parkinson's disease; LRRK2; Drosophila; Nurr1; Prostaglandin A2
• ISSN: 1535-1084; 1559-1174
• DOI: 10.1007/s12017-022-08712-3

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.