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Review
. 2022 Dec 19;23(24):16184.
doi: 10.3390/ijms232416184.

Advances in NURR1-Regulated Neuroinflammation Associated with Parkinson's Disease

Murad Al-Nusaif  1 , Yushan Lin  1 , Tianbai Li  1 , Cheng Cheng  1 , Weidong Le  1   2
Affiliations
Review

Advances in NURR1-Regulated Neuroinflammation Associated with Parkinson's Disease

Murad Al-Nusaif et al. Int J Mol Sci. .

Abstract

Neuroinflammation plays a crucial role in the progression of neurodegenerative disorders, particularly Parkinson's disease (PD). Glial cell activation and subsequent adaptive immune involvement are neuroinflammatory features in familial and idiopathic PD, resulting in the death of dopaminergic neuron cells. An oxidative stress response, inflammatory mediator production, and immune cell recruitment and activation are all hallmarks of this activation, leading to chronic neuroinflammation and progressive neurodegeneration. Several studies in PD patients' cerebrospinal fluid and peripheral blood revealed alterations in inflammatory markers and immune cell populations that may lead to or exacerbate neuroinflammation and perpetuate the neurodegenerative process. Most of the genes causing PD are also expressed in astrocytes and microglia, converting their neuroprotective role into a pathogenic one and contributing to disease onset and progression. Nuclear receptor-related transcription factor 1 (NURR1) regulates gene expression linked to dopaminergic neuron genesis and functional maintenance. In addition to playing a key role in developing and maintaining neurotransmitter phenotypes in dopaminergic neurons, NURR1 agonists have been shown to reverse behavioral and histological abnormalities in animal PD models. NURR1 protects dopaminergic neurons from inflammation-induced degeneration, specifically attenuating neuronal death by suppressing the expression of inflammatory genes in microglia and astrocytes. This narrative review highlights the inflammatory changes in PD and the advances in NURR1-regulated neuroinflammation associated with PD. Further, we present new evidence that targeting this inflammation with a variety of potential NURR1 target therapy medications can effectively slow the progression of chronic neuroinflammation-induced PD.

Keywords: Parkinson’s disease; astrocytes; microglia; neuroinflammation; nuclear receptor-related transcription factor 1.

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Conflict of interest statement

The authors declared no conflict of interest.

Figures

Figure 1
Figure 1
The figure highlights the inflammatory process in PD (↑: increase; ↓: decrease). The crosstalk between different cell types and intestinal dysbiosis with peripheral inflammation leads to increased circulating pro-inflammatory cytokines and immune cell activation. The hallmarks of a pro-inflammatory immune phenotype in PD include crossing the BBB and infiltrating immune cells from the periphery into the CNS. The two wavy, blue arrows indicate that dead or injured dopaminergic neurons and misfolded or aggregated proteins activate microglia and astrocytes, potentially resulting in a vicious circle. Abbreviations: BBB: blood-brain barrier; MHCI: major histocompatibility complex I; PD: Parkinson’s disease; ROS: reactive oxygen species.
Figure 2
Figure 2
NURR1-regulated Neuroinflammation associated with PD. The green arrows indicate the regulatory mechanism of NURR1: “sharp head (positive regulation), blunt head (negative regulation).” The black arrows are the main inflammatory pathways; NURR1 is involved in PD. α-Synuclein and NURR1 have a bidirectional effect. α-Synuclein boosts inflammatory mediators and free radicals, enhancing α-synuclein aggregation, resulting in a vicious cycle. NURR1 positively regulates several nuclear-encoded mitochondrial genes and protects cells from mitochondrial membranes and ROS. Abbreviations: ATP: adenosine triphosphate; CCL2: chemokine ligand 2; MMP: mitochondrial membrane potential; NURR1: nuclear receptor-related transcription factor 1; ROS: reactive oxygen species.
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