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

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.

Infectious Microorganisms Seen as Etiologic Agents in Parkinson’s Disease

“…Myelo-peroxidase, an oxidant-producing enzyme that might harm dopamine neurons, is released by astrocytes, and it has been suggested that astrocytes could control microglial multiplication by releasing the cytokine granulocyte macrophage colony-stimulating factor (GM-CSF) [ 34 ]. By contrast, the marked and considerable increase in microglial activation was already consistently seen in PD animal models and Parkinson’s disease postmortem investigations or MPTP-induced parkinsonism [ 35 , 36 , 37 ]. This stimulation and expansion of microglia is known as the neuroinflammatory characteristic of Parkinson’s disease.…”

“…Other researchers have elucidated and broadened the concept of neuroinflammation in Parkinson’s disease. TNF-alpha (tumor necrosis factor alpha), IL-1, IL-2, IL-4, IL-6, epidermal growth factor (EGF), converting growth factor alpha (TGF-alpha), TGF-1, and TGF-2 have been recognized at elevated levels in nigrostriatal areas of the CNS and ventricular cerebrospinal fluid of Parkinson’s disease patients, supposedly emerging from activated microglia [ 37 , 39 , 40 ]. Neuronal damage may need prolonged exposure to proinflammatory cytokines such as IL-1, according to one theory [ 41 ].…”

EP1 receptor: Devil in emperors coat

“…43 Although there are many reports that the EP1 receptor is neurotoxic and is involved in neurodegeneration through different mechanisms, it has also been found that the EP1 receptor is involved in the upregulation of Nur-related factor 1 (Nurr1) and regulates cell survival and proliferation. 44 Nurr1 plays an important function in the development and maintenance of midbrain DA neurons. 44 PGE2-activated EP1 stimulates Rho leading to the dissociation and activation of PKAc from multiprotein complex I-κB/nuclear factor-κB (NF-κB)/PKAc by phosphorylating I-κB.…”

“…44 Nurr1 plays an important function in the development and maintenance of midbrain DA neurons. 44 PGE2-activated EP1 stimulates Rho leading to the dissociation and activation of PKAc from multiprotein complex I-κB/nuclear factor-κB (NF-κB)/PKAc by phosphorylating I-κB. Activated PKAc then phosphorylates NF-κB and cyclic AMP response element-binding protein (CREB), resulting in increased expression of Nurr1 at the transcriptional and translational levels 45 (Figure 3).…”