Review
Parkinson's disease in the nuclear age of neuroinflammation

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Chronic neuroinflammation is associated with the pathophysiology of Parkinson's disease, a movement disorder characterised by deterioration of the nigrostriatal system of the brain. Recent studies have yielded important insights into the regulation of inflammation by nuclear receptors, a superfamily of ligand-activated transcription factors. Certain nuclear receptors are also emerging as regulators of neurodegeneration, including the degeneration of dopaminergic neurons in Parkinson's disease, and the importance of transcriptional control in this process is becoming increasingly apparent. Here, we discuss the role of Nurr1, peroxisome proliferator-activated receptors (PPARs), retinoic acid receptors, and glucocorticoid receptors in neuroinflammatory processes that contribute to dopaminergic neuronal degeneration. We examine current evidence providing insight into the potential of these important players as therapeutic targets for Parkinson's disease.

Section snippets

Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disease characterised primarily by the deterioration of motor activities that are controlled by the nigrostriatal system (Box 1). The resulting symptoms include tremors at rest, rigidity, bradykinesia, and postural instability [1]. Pathologically, PD is identified by the death of dopaminergic neurons which project from the substantia nigra (SN) to the striatum, leading to a marked decrease in dopaminergic neurotransmission to the striatum;

Nuclear hormone receptors involved in inflammation – potential therapeutic targets for Parkinson's disease?

Nuclear receptors (NRs) are ligand-activated transcription factors that regulate genes involved in physiological, metabolic, and developmental processes through their association with sequence-specific elements within the promoter regions of their target genes. Thus, they mediate transcriptional responses to hormones and other metabolic ligands. Several ligands of NRs are now in therapeutic use for breast cancer, diabetes, and inflammatory disorders. Recent investigations show that certain NRs

Concluding remarks

Therapeutic intervention for PD remains a major challenge. The rapidly emerging evidence that inflammation significantly contributes to the pathology of the disease places neuroinflammation as an important focus of research in PD, and consequently positions immunomodulatory therapies as prime targets for investigation. Specifically, approaches targeting the NRs that we have discussed here are proving particularly promising (Table 2). It is especially encouraging that some of these, such as

Acknowledgement

We apologise to all authors whose work in this field has not been cited owing to space limitations. We are grateful to John Cryan, Ian O’Brien, and Louise Collins for their helpful discussions.

Glossary

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
a chemical precursor to a neurotoxin that destroys dopaminergic neurons. In primates and mice, MPTP can be administered peripherally to produce laboratory models of PD. MPTP is not itself toxic, but it crosses the blood–brain barrier and is converted to the toxic cation 1-methyl-4-phenylpyridinium (MPP+) by the enzyme monoamine oxidase (MAO)-B in glial cells. MPP+ is taken up by dopaminergic neurons via the dopamine transporter protein on the

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