NURR1 in Parkinson disease—from pathogenesis to therapeutic potential

Decressac, Mickaël; Volakakis, Nikolaos; Björklund, Anders; Perlmann, Thomas

doi:10.1038/nrneurol.2013.209

Cited by 217 publications

(224 citation statements)

References 105 publications

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“…Although the presence of o-αSyn was not disclaimed in these studies, we advance that these changes might be a result of the presence of αSyn oligomers based on our own in vitro results. Using predictive databases, we found that human and mouse SYN1 and SYN2 promoters contained conserved putative responsive elements for CREB and Nurr1, respectively, two transcription factors involved in αSyn-mediated toxicity (29,30,63). We then found that the protein abundance of pS133-CREB and Nurr1 was decreased in association with the age-dependent accumulation of αSyn oligomers in TgI2.2 mice and following intraneuronal delivery of o-αSyn.…”

Section: Dependence On Endogenous αSyn For Exogenous O-αsyn To Inducementioning

confidence: 87%

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

Larson

Greimel

Amar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Mounting evidence indicates that soluble oligomeric forms of amyloid proteins linked to neurodegenerative disorders, such as amyloid-β (Aβ), tau, or α-synuclein (αSyn) might be the major deleterious species for neuronal function in these diseases. Here, we found an abnormal accumulation of oligomeric αSyn species in AD brains by custom ELISA, size-exclusion chromatography, and nondenaturing/denaturing immunoblotting techniques. Importantly, the abundance of αSyn oligomers in human brain tissue correlated with cognitive impairment and reductions in synapsin expression. By overexpressing WT human αSyn in an AD mouse model, we artificially enhanced αSyn oligomerization. These bigenic mice displayed exacerbated Aβ-induced cognitive deficits and a selective decrease in synapsins. Following isolation of various soluble αSyn assemblies from transgenic mice, we found that in vitro delivery of exogenous oligomeric αSyn but not monomeric αSyn was causing a lowering in synapsin-I/II protein abundance. For a particular αSyn oligomer, these changes were either dependent or independent on endogenous αSyn expression. Finally, at a molecular level, the expression of synapsin genes SYN1 and SYN2 was down-regulated in vivo and in vitro by αSyn oligomers, which decreased two transcription factors, cAMP response element binding and Nurr1, controlling synapsin gene promoter activity. Overall, our results demonstrate that endogenous αSyn oligomers can impair memory by selectively lowering synapsin expression.α-synuclein | oligomer | memory | Alzheimer's disease | synapsins

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Section: Dependence On Endogenous αSyn For Exogenous O-αsyn To Inducementioning

confidence: 87%

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

Larson

Greimel

Amar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…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).…”

Section: Resultsmentioning

confidence: 99%

“…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.…”

Section: Cografting Of Astrocytes Potentiates the Cell Therapeutic Efmentioning

confidence: 99%

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

Song¹,

Oh²,

Kwon³

et al. 2017

Journal of Clinical Investigation

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In this study, we have attempted to exploit the neurotrophic actions of astrocytes and Nurr1+Foxa2 functions in this cell type to improve the therapeutic outcomes of NPC transplantation using an animal model of PD. Our in vitro assays using a coculture system and conditioned media treatment revealed that astrocytes, especially those cultured from the ventral midbrain (VM), where HNF3β) is a potent cofactor that synergizes the Nurr1-mediated antiinflammatory roles in glia (16). Furthermore, forced coexpression of Nurr1 and Foxa2 (Nurr1+Foxa2) in glia promotes the synthesis and release of various neurotrophic factors, indicating that engineering of Nurr1 and Foxa2 in glia could become a powerful strategy for treating CNS disorders. Representative images of TH + DA neurons differentiated from VM-NPCs in the presence of Ctx-NPCs (control), Ctx-Ast, or VM-Ast. Scale bar: 100 μm. Insets, enlarged images of the boxed areas (original magnification, ×400). (C) DA neuronal yields at differentiation day 6 (D6). (D-H) Morphometric measurement of DA neuron maturity assessed by neurite outgrowth lengths (D), soma size (E), and by the Sholl test (F and G). In the Sholl analysis, the total number of neurite crossings was counted in each circle with the radius increasing in steps of 15 μm (F). The critical value (G) is the radius at which there was a maximum number of neurite crossings. *P < 0.05, significantly different from the control; # P < 0.05, significantly different from Ctx-Ast, 1-way ANOVA. n = 3-5 wells (C) and 100 (D and E) and 25-30 (F and G) TH + cells in each group.(H) Representative TH + neuronal morphologies reconstructed in 3D by Neurolucida. (I-L) Synaptic densities on TH + fibers. (I) Representative confocal images of synapsin + TH + fibers. Scale bar: 25 μm. Puncta positive for the synaptic vesicle-specific markers SV2 (J), synapsin (K), and bassoon (L) on TH + fibers were counted. *P < 0.05, significantly different from the control; # P < 0.05, significantly different from Ctx-Ast. n = 20 TH + fibers for each group. (M) Presynaptic DA release. n = 3 independent cultures. DA levels were measured in the media conditioned in the differentiated cultures for 24 hours (D13-D15) and in cultures evoked by KCl-mediated depolarization for 30 minutes. *P < 0.05; # P < 0.05, 1-way ANOVA. The Journal of Clinical Investigation R E S E A R C H A R T I C L E4 6 5 jci.org Volume 128 Number 1 January 2018 (Supplemental Figure 1B; supplemental material available online with this article; https://doi.org/10.1172/JCI93924DS1), immunocytochemical analyses revealed that major cell populations in the Ctx-and VM-astroglial cultures at day in vitro (DIV) 14 were positive for GFAP (85% and 82%), CD44 (79% and 76 %), GLT-1 (58% and 71 %), and GLAST protein (71% and 77%), respectively (Supplemental Figure 1A), except S100β (20% and 32%), a soluble protein associated with harmful reactivation of astrocytes (22). A few (0.24% ± 0.35% in Ctx-Ast and 0.43% ± 0.39% in VM-Ast, where Ast indicates astrocytes) and none of the cells in these c...

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“…A reduction in the electrical activity and of the excitability of DA neurons seems to augment their propensity to degenerate 12 . Nevertheless, the complexity of PD pathogenesis requires further studies to identify the mechanisms involved in DA neurons degeneration [13][14][15] .…”

Section: Introductionmentioning

confidence: 99%

Primary Culture of Mouse Dopaminergic Neurons

Gaven

Marin

Claeysen

2014

JoVE

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Dopaminergic neurons represent less than 1% of the total number of neurons in the brain. This low amount of neurons regulates important brain functions such as motor control, motivation, and working memory. Nigrostriatal dopaminergic neurons selectively degenerate in Parkinson's disease (PD). This progressive neuronal loss is unequivocally associated with the motors symptoms of the pathology (bradykinesia, resting tremor, and muscular rigidity). The main agent responsible of dopaminergic neuron degeneration is still unknown. However, these neurons appear to be extremely vulnerable in diverse conditions. Primary cultures constitute one of the most relevant models to investigate properties and characteristics of dopaminergic neurons. These cultures can be submitted to various stress agents that mimic PD pathology and to neuroprotective compounds in order to stop or slow down neuronal degeneration. The numerous transgenic mouse models of PD that have been generated during the last decade further increased the interest of researchers for dopaminergic neuron cultures. Here, the video protocol focuses on the delicate dissection of embryonic mouse brains. Precise excision of ventral mesencephalon is crucial to obtain neuronal cultures sufficiently rich in dopaminergic cells to allow subsequent studies. This protocol can be realized with embryonic transgenic mice and is suitable for immunofluorescence staining, quantitative PCR, second messenger quantification, or neuronal death/survival assessment. Video LinkThe video component of this article can be found at

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NURR1 in Parkinson disease—from pathogenesis to therapeutic potential

Cited by 217 publications

References 105 publications

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

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

Primary Culture of Mouse Dopaminergic Neurons

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