• Zhihao Mao, Yuning Zhang, Yirong Liang, Chenglai Xia, and Lan Tang.
• Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University (Foshan Maternity & Child Healthcare Hospital), Foshan 528000, China; NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
• Neuroscience. 2024 Nov 12; 560: 109119109-119.

AbstractParkinson's disease (PD) is the second most common neurodegenerative disorder whose etiology remains unknown. The immune system has been implicated in hallmarks of PD including aggregation of α-synuclein and death of dopaminergic neurons in the substantia nigra. As a core regulator of immune response and inflammation, liver X receptors (LXRs) have been shown to have protective effects in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. With two isoforms of LXRs (LXRα and LXRβ) expressed in the brain, their roles and distributions in this tissue remain largely unexplored. Here, we used MPTP to mimic symptoms and biomedical changes seen in PD in LXRα-/- and wild-type mice to investigate the role of LXRα in the etiology and progression of PD. We found that MPTP is unable to induce motor deficits, anxiety-like behavior in LXRα-/- mice, which has been seen in WT mice. Gene ontology analysis of RNA sequencing revealed that knockout of LXRα led to enrichment of the process, including immune response and inflammation in the midbrain. In addition, MPTP did not lead to dopaminergic neuron death in the striatum and substantia nigra in LXRα-/- mice, the basal GFAP protein level, and pro-inflammatory cytokines were elevated in LXRα-/- mice. Lastly, the microglia activation and astrogliosis caused by MPTP intoxication we found in WT mice were abolished in LXRα-/- mice. To sum up, we conclude that LXRα is a critical regulator in MPTP intoxication and may play a unique role in astrogliosis seen in the neuroinflammation of PD.Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.

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