Nurr1‐Based Therapies for Parkinson's Disease

Abstract

Previous studies have documented that orphan nuclear receptor Nurr1 (also known as NR4A2) plays important roles in the midbrain dopamine (DA) neuron development, differentiation and survival. Furthermore, it has been reported that the defects in Nurr1 are associated with Parkinson’s disease (PD). Thus, Nurr1 might be a potential therapeutic target for PD. Emerging evidence from in vitro and in vivo studies has recently demonstrated that Nurr1-activating compounds and Nurr1 gene therapy are able not only to enhance DA neurotransmission but also to protect DA neurons from cell injury induced by environmental toxin or microglia-mediated neuroinflammation. Moreover, modulators that interact with Nurr1 or regulate its function, such as retinoid X receptor, cyclic AMP-responsive element-binding protein, glial cell line-derived neurotrophic factor and Wnt/β-catenin pathway have the potential to enhance the effects of Nurr1-based therapies in PD. This review highlights the recent progress in preclinical studies of Nurr1-based therapies and discusses the outlook of this emerging therapy as a promising new generation of PD medication.

Cografting astrocytes improves cell therapeutic outcomes in a Parkinson’s disease model

“…Specifically, the differential expression patterns for the neurotrophic factors determined by quantitative PCR (qPCR) ( Figure 3N) were similarly replicated in the RNA-seq analyses ( Figure 4E), indicating fidelity of the RNAmDA neurons are specified based on the expression of several midbrain-specific genes, such as Nurr1, Foxa2, Lmx1a/b, Pitx3, and En1/2. As these midbrain markers play critical roles in DA phenotype maintenance, survival, and function (36)(37)(38)(39), their expression is critical in the preparation of mDA neurons for therapeutic purposes. However, we and others have recently shown that the expression of midbrain-specific markers in mDA neurons is largely affected by in vitro and in vivo environments and thus easily lost during passages, long after differentiation in vitro and after transplantation in vivo (16,40,41).…”

“…In the niche established by the VM-Ast, grafted NPCs efficiently differentiated into morphologically, synaptically, and functionally mature mDA neurons and the differentiated mDA neuronal cells survived for long periods after transplantation while maintaining expression of midbrain-specific markers. The expression of midbrain-specific factors such as Nurr1 and Foxa2 is a critical indicator for successful mDA neuron engraftment (49), as the expression of these genes is required for mDA neuron survival, function, and phenotype maintenance (36)(37)(38)(39). Considering that the expression of midbrain factors is easily lost in stressful conditions (16,40,41), sustained expression of midbrain markers in the presence of astrocytes is likely to be attained by the observed astrocyte actions that change the hostile inflammatory host brain milieu into a neurotrophic environment.…”

NR4A2 haploinsufficiency is associated with intellectual disability and autism spectrum disorder

“…NR4A2 is involved in several processes such as energy metabolism, cardiovascular diseases, inflammatory and immune responses, reproductive processes, development and homeostasis of the central nervous system . NR4A2 plays a role in the development, survival, and functional maintenance of dopaminergic cells of midbrain, the ventral tegmental area and the substantia nigra . Consequently, NR4A2 deficiency is associated with impaired dopaminergic function and increased vulnerability of midbrain dopaminergic neurons .…”

Mitochondrial dysfunction in Parkinson's disease

“…Retinoid X receptor, neurotropic factors derived from glial cell line, cyclic AMP‐responsive element binding protein and the Wnt/B‐ catenin pathway that interact with Nurr1 can be considered to have the potential to improve Nurr1 based therapies (Dong et al . ). Testing these molecular mechanisms in animal models and IPSC‐derived neurons represents a new therapeutic approach for PD.…”