Extended mutation analysis and association studies of Nurr1 (NR4A2) in Parkinson disease.
Hering R, Petrovic S, Mietz EM, Holzmann C, Berg D, Bauer P, Woitalla D, Müller T, Berger K, Krüger R, Riess O
This study investigates whether variations in the NR4A2 gene contribute to Parkinson disease risk in human populations. It provides direct genetic evidence linking NR4A2 to dopaminergic neuron health, which is relevant to understanding the biological mechanisms underlying your child's condition.
- Researchers analyzed NR4A2 mutations in patients with Parkinson disease.
- The study confirms NR4A2's role in dopaminergic neuron survival.
- Human genetic data supports NR4A2 as a key factor in brain development.
- Findings help distinguish between developmental and neurodegenerative impacts of the gene.
Transcription factors specifying dopamine phenotype are decreased in cocaine users.
Bannon MJ, Pruetz B, Barfield E, Schmidt CJ
Cocaine abuse reduces the levels of Nurr1 and Pitx3 proteins in adult human dopamine neurons, suggesting a loss of their specialized function. This finding highlights how environmental toxins can disrupt the same molecular pathways affected by NR4A2 mutations.
- Cocaine decreases Nurr1 and Pitx3 protein levels in human midbrain dopamine neurons.
- These transcription factors are essential for maintaining the dopaminergic phenotype in adults.
- The study uses post-mortem human brain tissue from cocaine users.
- Reduced protein abundance suggests a partial loss of dopamine neuron identity.
Congenital hypoventilation and impaired hypoxic response in Nurr1 mutant mice.
Nsegbe E, Wallén-Mackenzie A, Dauger S, Roux JC, Shvarev Y, Lagercrantz H, Perlmann T, Herlenius E
Mice lacking the Nurr1 gene exhibit severe breathing defects, including hypoventilation and an inability to increase breathing during low oxygen, which contributes to their early death. This study identifies respiratory control centers in the brainstem and carotid bodies as key sites where Nurr1 regulates these vital functions.
- Nurr1 knockout mice die within 24 hours due to severe respiratory failure.
- Newborns show hypoventilation, frequent apneas, and failed hypoxic breathing response.
- Heterozygous mice also display altered responses to low oxygen levels.
- Nurr1 is expressed in brainstem regions and carotid bodies controlling respiration.
- The findings link Nurr1 directly to the neural mechanisms of breathing adaptation.
Dopaminergic properties and experimental anti-parkinsonian effects of IPX750 in rodent models of Parkinson disease.
Jiang C, Wan X, Jankovic J, Christian ST, Pristupa ZB, Niznik HB, Sundsmo JS, Le W
IPX750, a pro-drug designed to improve dopamine delivery to the brain, reduces Parkinsonian symptoms in rodent models without causing neurotoxicity. The drug shows sustained anti-parkinsonian effects after treatment stops and preserves dopaminergic neurons in mice over eight weeks.
- IPX750 improves motor function in three different rodent models of Parkinson disease.
- The drug does not show neurotoxicity in cell cultures at effective doses.
- Anti-parkinsonian effects persist for about two weeks after stopping treatment.
- Eight weeks of treatment preserves dopamine-producing neurons in mouse brains.
p57(Kip2) cooperates with Nurr1 in developing dopamine cells.
Joseph B, Wallén-Mackenzie A, Benoit G, Murata T, Joodmardi E, Okret S, Perlmann T
The protein p57Kip2 works directly with Nurr1 to help midbrain dopamine cells mature, rather than just stopping cell division. This interaction is essential for the proper development of these specific neurons in mice.
- p57Kip2 expression depends on Nurr1 during dopamine cell development.
- Mice lacking p57Kip2 fail to mature midbrain dopamine neurons properly.
- p57Kip2 binds directly to Nurr1 to drive neuronal maturation.
- This mechanism operates independently of p57Kip2's role in stopping cell division.
Familial Parkinson's disease: a hint to elucidate the mechanisms of nigral degeneration.
Hattori N, Kobayashi H, Sasaki-Hatano Y, Sato K, Mizuno Y
This review identifies NR4A2 as one of five causative genes for familial Parkinson's disease, highlighting its role in a rare dominant form with dopa-responsive features. It positions NR4A2 within the broader genetic landscape of Parkinson's, suggesting that understanding these specific gene defects helps explain the diverse mechanisms behind nigral degeneration.
- NR4A2 is identified as a causative gene for familial Parkinson's disease.
- Mutations in NR4A2 cause a rare dominant form with dopa-responsive parkinsonian features.
- The paper reviews five known causative genes including alpha-Synuclein, parkin, UCHL1, and DJ-1.
- Different genetic causes suggest Parkinson's is heterogeneous but may share common pathways like ubiquitin-proteasome function.
A common NURR1 polymorphism associated with Parkinson disease and diffuse Lewy body disease.
Zheng K, Heydari B, Simon DK
This study links a common genetic variation in the NR4A2 gene to an increased risk of developing Parkinson disease and diffuse Lewy body disease in adults. The heterozygous form of this variant doubles the risk for Parkinson disease, particularly in early-onset cases.
- Heterozygous NI6P increases Parkinson disease risk by approximately two-fold.
- The variant shows a stronger association with early-onset Parkinson disease.
- Homozygous NI6P appears linked to diffuse Lewy body disease, though results are borderline.
- This is human genetic evidence connecting NR4A2 variants to adult neurodegenerative conditions.
The control of dopamine neuron development, function and survival: insights from transgenic mice and the relevance to human disease.
Eells JB
This review summarizes how knockout mice lacking Nurr1 (NR4A2) or other dopamine-related genes help researchers understand the development and survival of dopamine neurons. It highlights that these animal models provide insights into human conditions like Parkinson's disease, schizophrenia, and ADHD by showing how gene loss affects neurotransmission.
- The paper reviews mouse models lacking Nurr1 to explain dopamine neuron biology.
- It connects genetic disruptions in mice to human disorders like Parkinson's and ADHD.
- Understanding these mechanisms may eventually guide treatments for related human diseases.
Genetic engineering of mouse embryonic stem cells by Nurr1 enhances differentiation and maturation into dopaminergic neurons.
Chung S, Sonntag KC, Andersson T, Bjorklund LM, Park JJ, Kim DW, Kang UJ, Isacson O, Kim KS
Forcing Nurr1 expression in mouse stem cells significantly increases the yield and maturation of dopamine-producing neurons. This approach enhances the production of midbrain dopaminergic phenotypes that release dopamine in response to stimulation.
- Nurr1 overexpression boosts dopamine neuron generation by four to five times in mouse stem cells.
- The resulting neurons express key midbrain markers and do not produce other neurotransmitters like GABA.
- Combined with specific growth factors, Nurr1 further increases the number of mature dopamine neurons.
- These engineered neurons successfully produce and release dopamine upon electrical stimulation.
Nurr1-null heterozygous mice have reduced mesolimbic and mesocortical dopamine levels and increased stress-induced locomotor activity.
Eells JB, Lipska BK, Yeung SK, Misler JA, Nikodem VM
Mice with one non-functional copy of the Nurr1 gene show reduced dopamine in brain areas linked to emotion and stress, along with increased movement when stressed. This suggests that having only one working NR4A2 gene may disrupt dopamine signaling in specific neural pathways relevant to behavioral regulation.
- One missing NR4A2 copy lowers dopamine in the prefrontal cortex and nucleus accumbens.
- Striatum dopamine levels remain unchanged, indicating selective pathway vulnerability.
- Mice exhibit heightened locomotor activity in response to mild stress.
- This effect persists from childhood into adulthood in the mouse model.
Association of homozygous 7048G7049 variant in the intron six of Nurr1 gene with Parkinson's disease.
Xu PY, Liang R, Jankovic J, Hunter C, Zeng YX, Ashizawa T, Lai D, Le WD
This study identifies a specific genetic variant in the NR4A2 gene that is more common in people with Parkinson's disease than in healthy individuals. The research confirms that this variant is associated with typical Parkinson's disease symptoms and onset age.
- Researchers sequenced the NR4A2 gene in humans with familial and sporadic Parkinson's disease.
- A homozygous variant in intron 6 was significantly more frequent in patients than controls.
- Patients with this variant showed typical Parkinson's disease clinical features.
- The study provides human genetic evidence linking NR4A2 variants to Parkinson's risk.
Mutation analysis of the retinoid X receptor beta, nuclear-related receptor 1, and peroxisome proliferator-activated receptor alpha genes in schizophrenia and alcohol dependence: possible haplotype association of nuclear-related receptor 1 gene to alcohol dependence.
Ishiguro H, Okubo Y, Ohtsuki T, Yamakawa-Kobayashi K, Arinami T
This study identifies specific genetic variations in the NR4A2 gene that are associated with alcohol dependence in a Japanese cohort. It confirms that the NR4A2 locus contributes to genetic susceptibility for this condition, though it does not address the neurodevelopmental symptoms typical of NR4A2 syndrome.
- Researchers screened NR4A2 and related genes in patients with schizophrenia and alcohol dependence.
- They found specific polymorphisms and a haplotype in NR4A2 linked to alcohol dependence.
- No association was found between the other tested genes and either disease.
- The study focuses on addiction genetics rather than developmental or motor phenotypes.
Mutation analysis of the human NR4A2 gene, an essential gene for midbrain dopaminergic neurogenesis, in schizophrenic patients.
Chen YH, Tsai MT, Shaw CK, Chen CH
This study screens the NR4A2 gene in patients with schizophrenia and identifies rare variants that may contribute to the disorder. It does not provide information on the specific neurodevelopmental or motor phenotypes associated with NR4A2 mutations in children.
- Researchers sequenced the NR4A2 gene in Chinese schizophrenic patients.
- Two variants were found, one common and one rare in two patients.
- The rare variant was not present in healthy control subjects.
- Findings suggest NR4A2 variants might influence schizophrenia risk.
- Study focuses on psychiatric outcomes, not developmental or motor symptoms.
Orphan nuclear receptor Nurr1 is essential for Ret expression in midbrain dopamine neurons and in the brain stem.
Wallén A A, Castro DS, Zetterström RH, Karlén M, Olson L, Ericson J, Perlmann T
Nurr1 directly controls the expression of the Ret receptor, which is critical for the proper development and migration of dopamine neurons in the brain. This mechanism explains why Nurr1 deficiency leads to the loss of these specific nerve cells during embryonic growth.
- Nurr1 regulates Ret gene expression in midbrain dopamine neurons.
- Ret signaling guides dopamine cell migration and target innervation.
- Nurr1 also controls Ret in vagus nerve brain stem nuclei.
- Loss of Nurr1 disrupts this pathway, causing developmental deficits.
Differentiation of embryonic stem cell-derived dopaminergic neurons is enhanced by survival-promoting factors.
Rolletschek A, Chang H, Guan K, Czyz J, Meyer M, Wobus AM
Survival-promoting factors increase the number and viability of dopamine-producing neurons derived from mouse embryonic stem cells. These factors boost key molecular markers for dopaminergic identity and protect the cells from death during development.
- Mouse stem cells become viable dopamine-producing neurons when treated with specific survival factors.
- Factors like GDNF and IL-1beta significantly raise Nurr1 and tyrosine hydroxylase mRNA levels.
- The anti-apoptotic gene bcl-2 increases, helping the new neurons survive terminal differentiation stages.
- Treated cultures show more dopamine transporter-positive cells but not other neurotransmitter types.
- Intracellular dopamine production is detectable in these enhanced stem cell-derived neurons.
Nigrostriatal innervation is preserved in Nurr1-null mice, although dopaminergic neuron precursors are arrested from terminal differentiation.
Witta J, Baffi JS, Palkovits M, Mezey E, Castillo SO, Nikodem VM
Nurr1 is essential for the final maturation of dopamine-producing neurons but does not prevent their initial formation, survival, or connection to the striatum. This suggests that activating Nurr1 could potentially help mature these neurons in conditions like Parkinson's disease.
- Nurr1 loss stops dopamine neurons from fully maturing.
- Early neuron development and survival remain normal without Nurr1.
- Neurons still form correct connections to the striatum.
- The study uses mice, not human patients.
- Findings suggest potential therapeutic activation of Nurr1.
NURR1 mutations in cases of schizophrenia and manic-depressive disorder.
Buervenich S, Carmine A, Arvidsson M, Xiang F, Zhang Z, Sydow O, Jönsson EG, Sedvall GC, Leonard S, Ross RG, Freedman R, Chowdari KV, Nimgaonkar VL, Perlmann T, Anvret M, Olson L
This study identifies rare NURR1 mutations in patients with schizophrenia and bipolar disorder, demonstrating that these specific genetic changes reduce the protein's ability to activate gene transcription. The findings suggest that partial loss of NURR1 function may contribute to psychiatric conditions involving dopamine pathways, distinct from the neurodevelopmental phenotypes seen in NR4A2-related syndromes.
- Researchers sequenced the NURR1 gene in patients with schizophrenia and manic-depressive disorder.
- Three missense mutations were found, all reducing transcriptional activity by 30-40%.
- These specific mutations were absent in Parkinson's disease patients and healthy controls.
- The study links reduced NURR1 function to psychiatric disorders rather than motor deficits.
Selective increase of Nurr1 mRNA expression in mesencephalic dopaminergic neurons of D2 dopamine receptor-deficient mice.
Tseng KY, Roubert C, Do L, Rubinstein M, Kelly MA, Grandy DK, Low MJ, Gershanik OS, Murer MG, Giros B, Raisman-Vozari R
Removing D2 dopamine receptors in mice causes a specific increase in Nurr1 (NR4A2) mRNA levels within the brain's dopaminergic neurons. This suggests that normal dopamine signaling through D2 receptors suppresses NR4A2 expression, and this feedback loop is disrupted when the receptor is absent.
- D2 dopamine receptor absence increases Nurr1 mRNA in mesencephalic dopaminergic neurons.
- No change in Nurr1 occurs in other brain regions like the cortex or habenula.
- The finding implies dopamine acts via D2 receptors to regulate NR4A2 levels.
- This is a mechanistic study in mice, not a clinical trial or human cohort.
A second independent pathway for development of mesencephalic dopaminergic neurons requires Lmx1b.
Smidt MP, Asbreuk CH, Cox JJ, Chen H, Johnson RL, Burbach JP
The transcription factor Lmx1b drives a separate developmental pathway from Nurr1 (NR4A2) that is essential for the long-term survival of midbrain dopamine neurons. While Nurr1 helps establish the basic identity of these cells, loss of Lmx1b causes them to disappear during embryonic development despite initial formation.
- Lmx1b and NR4A2 regulate distinct pathways in midbrain dopamine neuron development.
- Lmx1b is required for Ptx3 expression and long-term survival of these neurons.
- Loss of Lmx1b leads to embryonic loss of dopamine neurons despite Nurr1 presence.
Fate of mesencephalic AHD2-expressing dopamine progenitor cells in NURR1 mutant mice.
Wallén A, Zetterström RH, Solomin L, Arvidsson M, Olson L, Perlmann T
NURR1 is essential for the survival, migration, and proper connection of dopamine-producing neurons in the developing brain. Without NURR1, these cells fail to mature or reach their target areas, leading to a loss of dopaminergic function.
- NURR1 is not required for early dopamine cell identity but is critical for later maturation.
- Lack of NURR1 causes dopamine neurons to die or fail to migrate correctly.
- Neurons cannot properly innervate the striatum without functional NURR1.
- This study uses mouse models, not human patients.
Selective agenesis of mesencephalic dopaminergic neurons in Nurr1-deficient mice.
Le W, Conneely OM, Zou L, He Y, Saucedo-Cardenas O, Jankovic J, Mosier DR, Appel SH
Mice lacking the Nurr1 gene lose all dopamine-producing neurons in specific brain regions, mirroring the neuronal loss seen in Parkinson's disease. This confirms that Nurr1 is strictly required for the development of these particular cells but does not affect other neurotransmitter systems.
- Nurr1-deficient mice completely lack dopamine neurons in the substantia nigra and ventral tegmental area.
- Dopamine levels drop by 98% in the striatum, a key motor control region.
- Other neurotransmitter systems like serotonin and norepinephrine remain largely unaffected.
- The specific neuronal loss pattern resembles Parkinson's disease pathology.
Induction of a midbrain dopaminergic phenotype in Nurr1-overexpressing neural stem cells by type 1 astrocytes.
Wagner J, Akerud P, Castro DS, Holm PC, Canals JM, Snyder EY, Perlmann T, Arenas E
Overexpressing the Nurr1 protein in neural stem cells, combined with signals from astrocytes, successfully converts these cells into dopamine-producing neurons that resemble those found in the human brain. This method generates a large supply of transplantable dopaminergic cells, offering a potential cell-replacement therapy for Parkinson's disease.
- Nurr1 overexpression plus astrocyte factors creates functional dopamine neurons from stem cells.
- Over 80% of treated cells match the phenotype of natural midbrain dopamine neurons.
- The process yields unlimited cell numbers suitable for transplantation in animal models.
- This approach targets neuronal replacement strategies for Parkinson's disease.
Differential expression of tyrosine hydroxylase in catecholaminergic neurons of neonatal wild-type and Nurr1-deficient mice.
Baffi JS, Palkovits M, Castillo SO, Mezey E, Nikodem VM
Nurr1 is required for the production of tyrosine hydroxylase in specific midbrain dopamine neurons, as its absence leads to a complete loss of this enzyme in those regions. However, Nurr1 is not necessary for tyrosine hydroxylase expression in other dopamine neuron groups, indicating distinct regulatory mechanisms across different brain areas. This study confirms that Nurr1 deficiency specifically disrupts the dopaminergic pathway in the substantia nigra and ventral tegmental area.
- Nurr1 absence eliminates tyrosine hydroxylase in midbrain dopamine neurons.
- Nurr1 is not required for tyrosine hydroxylase in other dopamine groups.
- Nurr1 expression is restricted to specific catecholaminergic cell subsets.
- The study maps Nurr1's role in dopamine biosynthesis regulation.
Dopamine biosynthesis is selectively abolished in substantia nigra/ventral tegmental area but not in hypothalamic neurons in mice with targeted disruption of the Nurr1 gene.
Castillo SO, Baffi JS, Palkovits M, Goldstein DS, Kopin IJ, Witta J, Magnuson MA, Nikodem VM
Mice lacking the Nurr1 gene lose dopamine production in brain regions critical for movement but retain it in other areas, and these mice die shortly after birth. Supplementing with L-DOPA does not save the mice or restore dopamine levels, indicating that Nurr1 is required for more than just providing the substrate for dopamine synthesis.
- Nurr1-null mice die within 24 hours of birth.
- Dopamine and its synthetic enzymes are absent in substantia nigra and VTA.
- L-DOPA treatment fails to rescue the mice or restore dopamine.
- Hypothalamic dopamine neurons remain unaffected by the gene loss.
- Nurr1 is essential for fetal development and postnatal survival.
Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons.
Saucedo-Cardenas O, Quintana-Hau JD, Le WD, Smidt MP, Cox JJ, De Mayo F, Burbach JP, Conneely OM
This study establishes that the Nurr1 protein is required for both the final maturation and survival of developing dopamine-producing neurons in mice. Without Nurr1, these precursor cells fail to become fully functional dopamine neurons and subsequently die.
- Nurr1 drives late-stage differentiation of dopamine neuron precursors in mouse embryos.
- Lack of Nurr1 prevents precursors from acquiring a complete dopaminergic phenotype.
- Precursor cells degenerate via apoptosis when Nurr1 is absent during development.
- This confirms Nurr1's essential role in generating and maintaining midbrain dopamine neurons.
Dopamine neuron agenesis in Nurr1-deficient mice.
Zetterström RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlmann T
Mice lacking the Nurr1 gene fail to develop midbrain dopamine neurons and die shortly after birth, while those with only one working copy have reduced dopamine levels but survive. This establishes that Nurr1 is essential for creating these specific brain cells, which are critical for movement and behavior. The findings suggest that drugs targeting Nurr1 might help treat Parkinson's disease or similar conditions involving dopamine loss.
- Mice without Nurr1 do not develop midbrain dopamine neurons.
- Nurr1-deficient mice are hypoactive and die soon after birth.
- Heterozygous mice have lower dopamine levels but appear healthy.
- Nurr1 is required for the formation of dopamine-producing cells.