NURR1 in Parkinson disease—from pathogenesis to therapeutic potential

• Published in: Nature reviews. Neurology Vol. 9; no. 11; pp. 629 - 636
• Main Authors: Decressac, Mickael, Volakakis, Nikolaos, Björklund, Anders, Perlmann, Thomas
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2013; Nature Publishing Group
• Subjects: 631/378/2583; 692/699/375/365/1718; Ablation; Animals; Brain; Care and treatment; Clinical Medicine; Development and progression; Dopamine; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Genetic aspects; Health aspects; Humans; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Mesencephalon - metabolism; Mesencephalon - pathology; Mutation; Neurologi; Neurology; Neurons; Nuclear Receptor Subfamily 4, Group A, Member 2 - genetics; Nuclear Receptor Subfamily 4, Group A, Member 2 - metabolism; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Pathogenesis; Pathology; Physiological aspects; review-article; Risk factors; Transcription factors; Sweden
• ISSN: 1759-4758; 1759-4766; 1759-4766
• DOI: 10.1038/nrneurol.2013.209

Parkinson disease (PD) pathogenesis involves dysfunction and eventual death of midbrain dopaminergic neurons. Emerging evidence points to a role for the transcription factor NURR1 in this process. In this Review, the authors describe findings from animal and human studies that support this concept, outline possible underlying mechanisms involving oxidative stress and interaction with α-synuclein, and highlight the potential of NURR1 as a therapeutic target. In Parkinson disease (PD), affected midbrain dopamine (DA) neurons lose specific dopaminergic properties before the neurons die. How the phenotype of DA neurons is normally established and the ways in which pathology affects the maintenance of cell identity are, therefore, important considerations. Orphan nuclear receptor NURR1 (NURR1, also known as NR4A2) is involved in the differentiation of midbrain DA neurons, but also has an important role in the adult brain. Emerging evidence indicates that impaired NURR1 function might contribute to the pathogenesis of PD: NURR1 and its transcriptional targets are downregulated in midbrain DA neurons that express high levels of the disease-causing protein α-synuclein. Clinical and experimental data indicate that disrupted NURR1 function contributes to induction of DA neuron dysfunction, which is seen in early stages of PD. The likely involvement of NURR1 in the development and progression of PD makes this protein a potentially interesting target for therapeutic intervention. Key Points NURR1 and other transcription factors that are essential for the development and specification of midbrain dopamine neurons during development continue to have an important role in the adult brain Deletion of NURR1 in mature dopamine neurons results in progressive pathology, reduction in dopamine neuron markers and motor impairments—recapitulating early features of Parkinson disease Ablation of Nurr1 in adult rodents results in reduced expression of genes associated with mitochondrial function and oxidative phosphorylation, suggesting a role for Nurr1 in the maintenance of midbrain dopamine neurons NURR1 and its transcriptional targets are downregulated in midbrain dopamine neurons that express high levels of the disease-causing protein α-synuclein, as observed in rodent models and patients with Parkinson disease α-Synuclein overexpression results in an almost complete blockade of GDNF trophic signalling and failure of GDNF to protect against α-synuclein-induced toxicity in affected neurons Reduced NURR1 expression might result in induction of dopamine neuron dysfunction as well progression of degenerative changes, which could make this protein a promising therapeutic target