Top

Published in:

01-10-2016 | Short Communication

Altered NR4A Subfamily Gene Expression Level in Peripheral Blood of Parkinson’s and Alzheimer’s Disease Patients

Authors: Francesca Montarolo, Simona Perga, Serena Martire, Désirée Nicole Navone, Alberto Marchet, Daniela Leotta, Antonio Bertolotto

Published in: Neurotoxicity Research | Issue 3/2016

Abstract

Parkinson’s disease (PD) is a neurodegenerative pathology characterized by the degeneration of midbrain dopamine neurons, whose development and maintenance in brain is related to the transcription factor NR4A2 (also called Nurr1). Notably, NR4A2 is a neuroprotective agent with anti-inflammatory role in microglia and astrocytes. Furthermore, mutations in NR4A2 gene are associated to the familial form of PD, and its gene expression level is down-regulated in blood obtained from PD patients. NR4A2 belongs to the NR4A subfamily consisting of three members: NR4A1, NR4A2, and NR4A3. The NR4A subfamily shares high degree of homology in their molecular structure and cooperates in a spectrum of functions ranging from central nervous system to immune control during physiological and pathological conditions. Considering the close functional link between the member of NR4A subfamily, we performed a gene expression analysis of NR4A1, NR4A2, and NR4A3 in peripheral blood obtained from PD patients and healthy controls (HC). Then, in order to evaluate possible involvement of the NR4A subfamily in other neurodegenerative processes, we carried out the same analysis on blood obtained from Alzheimer’s disease (AD) patients. A correlation between clinical features and gene expression was also evaluated. We found a marked down-regulated gene expression of the NR4A subfamily obtained from PD patients, but only a NR4A1 decrease in AD patients compared to HC. This study reports that the entire NR4A subfamily and not only NR4A2 could be systemically involved in PD suggesting that the study of these factors could be a promising approach to develop PD therapy.

Available only for authorised users

Achiron A, Grotto I, Balicer R, Magalashvili D, Feldman A, Gurevich M (2010) Microarray analysis identifies altered regulation of nuclear receptor family members in the pre-disease state of multiple sclerosis. Neurobiol Dis 38(2):201–209CrossRefPubMed

Achiron A, Feldman A, Gurevich M (2011) Characterization of the multiple sclerosis traits: nuclear receptors (NR) impaired apoptosis pathway and the role of 1-alpha 25-dihydroxyvitamin D3. J Neurol Sci 311(1):9–14CrossRefPubMed

Castro DS, Hermanson E, Joseph B, Wallen A, Aarnisalo P, Heller A, Perlmann T (2001) Induction of cell cycle arrest and morphological differentiation by Nurr1 and retinoids in dopamine MN9D cells. J Biol Chem 276:43277–43284CrossRefPubMed

Chu Y, Kompoliti K, Cochran EJ, Mufson EJ, Kordower JH (2002) Age-related decreases in Nurr1 immunoreactivity in the human substantia nigra. J Comp Neurol 450:203–214CrossRefPubMed

De Miranda BR, Popichak KA, Hammond SL, Miller JA, Safe S, Tjalkens RB (2014) Novel para-phenyl substituted diindolylmethanes protect against MPTP neurotoxicity and suppress glial activation in a mouse model of Parkinson’s disease. Toxicol Sci 143(2):360–373CrossRefPubMedPubMedCentral

de Urquiza AM, Liu S, Sjoberg M, Zetterstrom RH, Griffiths W, Sjovall J, Perlmann T (2000) Docosahexaenoic acid, a ligand for the retinoid X receptor in mouse brain. Science 290:2140–2144CrossRefPubMed

Decressac M, Kadkhodaei B, Mattsson B, Laguna A, Perlmann T, Bjorklund A (2012) α-Synuclein-induced down-regulation of Nurr1 disrupts GDNF signaling in nigral dopamine neurons. Sci Transl Med 163:ra156

Giguère V (1999) Orphan nuclear receptors: from gene to function 1. Endocr Rev 20(5):689–725PubMed

Gilli F, Lindberg RL, Valentino P, Marnetto F, Malucchi S, Sala A, Capobianco M, Di Sapio A, Sperli F, Kappos L, Calogero RA, Bertolotto A (2010) Learning from nature: pregnancy changes the expression of inflammation-related genes in patients with multiple sclerosis. PlosOne 5(1):e8962CrossRef

Gilli F, Navone ND, Perga S, Marnetto F, Caldano M, Capobianco M, Pulizzi A, Malucchi S, Bertolotto A (2011) Loss of braking signals during inflammation: a factor affecting the development and disease course of multiple sclerosis. Arch Neurol 68(7):879–888CrossRefPubMed

Hammond SL, Safe S, Tjalkensa RB (2015) A novel synthetic activator of Nurr1 induces dopaminergic gene expression and protects against 6-hydroxydopamine neurotoxicity in vitro. Neurosci Lett 607:83–89CrossRefPubMedPubMedCentral

Hawk JD, Bookout AL, Poplawski SG, Bridi M, Rao AJ, Sulewski ME, Kroener BT, Manglesdorf DJ, Abel T (2012) NR4A nuclear receptors support memory enhancement by histone deacetylase inhibitors. J Clin Invest 122(10):3593–3602CrossRefPubMedPubMedCentral

Hering R, Petrovic S, Mietz EM, Holzmann C, Berg D, Bauer P, Woitalla D, Müller T, Berger K, Krüger R, Riess O (2004) Extended mutation analysis and association studies of Nurr1 (NR4A2) in Parkinson disease. Neurology 62:1231–1232CrossRefPubMed

Kadkhodaei B, Ito T, Joodmardi E, Mattsson B, Rouillard C, Carta M, Muramatsu S, Sumi-Ichinose C, Nomura T, Metzger D, Chambon P, Lindqvist E, Larsson NG, Olson L, Björklund A, Ichinose H, Perlmann T (2009) Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons. J Neurosci 29(50):15923–15932CrossRefPubMed

Kadkhodaei B, Alvarsson A, Alvarsson A, Schintu N, Ramskold D, Volakakis N, Joodmardi E, Yoshitake T, Kehr J, Decressac M, Bjorklund A, Sandberg R, Svenningsson P, Perlmann T (2013) Transcription factor Nurr1 maintains fiber integrity and nuclear-encoded mitochondrial gene expression in dopamine neurons. Proc Natl Acad Sci USA 110:2360–2365CrossRefPubMedPubMedCentral

Law SW, Conneely OM, DeMayo FJ, O’Malley BW (1992) Identification of a new brain-specific transcription factor, NURR1. Mol Endocrinol 6(12):2129–2135PubMed

Le W, Xu P, Jankovic J, Jiang H, Appel SH, Smith RG, Vassilatis DK (2003) Mutations in NR4A2 associated with familial Parkinson disease. Nat Genet 33:85–89CrossRefPubMed

Le W, Pan T, Huang M, Xu P, Xie W, Zhu W, Zhang X, Deng H, Jankovic J (2008) Decreased NURR1 gene expression in patients with Parkinson’s disease. J Neurol Sci 273:29–33CrossRefPubMedPubMedCentral

Li QX, Ke N, Sundaram R, Wong-Staal F (2006) NR4A1, 2, 3-an orphan nuclear hormone receptor family involved in cell apoptosis and carcinogenesis. Histol Histopathol 21:533–540PubMed

Liu H, Wei L, Tao Q, Deng H, Ming M, Xu P, Le W (2012) Decreased NURR1 and PITX3 gene expression in Chinese patients with Parkinson’s disease. Eur J Neurol 19:870–875CrossRefPubMed

Liu H, Tao Q, Deng H, Ming M, Ding Y, Xu P, Chen S, Song Z, Le W (2013) Genetic analysis of NR4A2 gene in a large population of Han Chinese patients with Parkinson’s disease. Eur J Neurol 20(3):584–587CrossRefPubMed

Malewicz M, Kadkhodaei B, Kee N, Volakakis N, Hellman U, Viktorsson K, Leung CY, Chen B, Lewensohn R, van Gent DC, Chen DJ, Perlmann T (2011) Essential role for DNA-PK-mediated phosphorylation of NR4A nuclear orphan receptors in DNA double-strand break repair. Genes Dev 25:2031–2040CrossRefPubMedPubMedCentral

McMorrow JP, Murphy EP (2011) Inflammation: a role for NR4A orphan nuclear receptors? Biochem Soc Trans 39:688–693CrossRefPubMed

McNulty SE, Barrett RM, Vogel-Ciernia A, Malvaez M, Hernandez N, Davatolhagh MF, Matheos DP, Schiffman A, Wood MA (2012) Differential roles for Nr4a1 and Nr4a2 in object location versus object recognition long-term memory. Learn Mem 19(12):588–592CrossRefPubMedPubMedCentral

Meissner WG (2011) Priorities in Parkinson’s disease research. Nat Rev Drug Discov 10(5):377–393CrossRefPubMed

Milbrandt J (1988) Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene. Neuron 1(3):183–188CrossRefPubMed

Mohan H, Aherne CM, Rogers AC, Baird AW, Winter DC, Murphy EP (2012) Molecular pathways: the role of NR4A orphan nuclear receptors in cancer. Clin Cancer Res 18:3223–3228CrossRefPubMed

Mullican SE, Zhang S, Konopleva M (2007) Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia. Nat Med 13:730–735CrossRefPubMed

Navone ND, Perga S, Martire S, Berchialla P, Malucchi S, Bertolotto A (2014) Monocytes and CD4+ T cells contribution to the under-expression of NR4A2 and TNFAIP3 genes in patients with Multiple Sclerosis. J Neuroimmunol 272(1–2):99102

Oh S, Chang M, Song J, Rhee Y, Joe E, Lee H, Yi Lee S (2015) Combined Nurr1 and Foxa2 roles in the therapy of Parkinson’s disease. EMBO Mol Med 7:510–525CrossRefPubMedPubMedCentral

Ohkura N, Hijikuro M, Yamamoto A, Miki K (1994) Molecular cloning of a novel thyroid/steroid receptor superfamily gene from cultured rat neuronal cells. Biochem Biophys Res Commun 205(3):1959–1965CrossRefPubMed

Pèrez-Sieira S, Lòpez M, Nogueiras R, Tovar S (2014) Regulation of NR4A by nutritional status, gender, postnatal development and hormonal deficiency. Sci Rep 4:4264CrossRefPubMedPubMedCentral

Perlmann T, Jansson L (1995) A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1. Genes Dev 9:769–782CrossRefPubMed

Reynolds AD, Banerjee R, Liu J, Gendelman HE, Mosley RL (2007) Neuroprotective activities of CD4+ CD25+ regulatory T cells in an animal model of Parkinson’s disease. J Leukoc Biol 82(5):1083–1094CrossRefPubMed

Safe S, Jin U, Morpurgo B, Abudayyeh A, Singh M, Tjalkens RB (2015) Nuclear receptor 4A (NR4A) family—orphans no more. J Steroid Biochem Mol Biol 157:48–60CrossRefPubMed

Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, Gage FH, Glass CK (2009) A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137:47–59CrossRefPubMedPubMedCentral

Sekiya T, Kashiwagi I, Inoue N, Morita R, Hori S, Waldmann H, Rudensky AY, Ichinose H, Metzger D, Chambon P, Yoshimura A (2011) The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells. Nat Comm 2:269CrossRef

Sekiya T, Kashiwagi I, Yoshida R, Fukaya T, Morita R, Kimura A, Ichinose H, Metzger D, Chambon P, Yoshimura A (2013) Nr4a receptors are essential for thymic regulatory T cell development and immune homeostasis. Nat Immunol 14(3):230–237CrossRefPubMed

Volakakis N, Kadkhodaei B, Joodmardi E, Wallis K, Panman L, Silvaggi J, Spiegelman BM, Perlmann T (2010) NR4A orphan nuclear receptors as mediators of CREB-dependent neuroprotection. Proc Natl Acad Sci USA 107:12317–12322CrossRefPubMedPubMedCentral

Wang Z, Benoit G, Liu J, Prasad S, Aarnisalo P, Liu X, Xu H, Walker NP, Perlmann T (2003) Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors. Nature 423(6939):555–560CrossRefPubMed

Wenzl K, Troppan K, Neumeister P, Deutsch AJA (2015) The nuclear orphan receptor NR4A1 and NR4A3 as tumor suppressors in hematologic neoplasms. Curr Drug Targ. 16:38–46CrossRef

Zetterstrom RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlman T (1997) Dopamine neuron agenesis in Nurr1-deficient mice. Science 276:248–250CrossRefPubMed

Zheng K, Heydari B, Simon DK (2003) A common NURR1 polymorphism associated with Parkinson disease and diffuse Lewy body disease. Arch Neurol 60:722–725CrossRefPubMed

Title: Altered NR4A Subfamily Gene Expression Level in Peripheral Blood of Parkinson’s and Alzheimer’s Disease Patients
Authors: Francesca Montarolo
Simona Perga
Serena Martire
Désirée Nicole Navone
Alberto Marchet
Daniela Leotta
Antonio Bertolotto
Publication date: 01-10-2016
Publisher: Springer US
Published in: Neurotoxicity Research / Issue 3/2016
Print ISSN: 1029-8428
Electronic ISSN: 1476-3524
DOI: https://doi.org/10.1007/s12640-016-9626-4

At a glance: The STEP trials

Springer Medicine

Altered NR4A Subfamily Gene Expression Level in Peripheral Blood of Parkinson’s and Alzheimer’s Disease Patients

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2016

β-Ecdysterone Protects SH-SY5Y Cells Against 6-Hydroxydopamine-Induced Apoptosis via Mitochondria-Dependent Mechanism: Involvement of p38MAPK–p53 Signaling Pathway

Chemotherapy-Induced Neurotoxicity: Evidence of a Protective Role of CC Homozygosis in the Interleukin-1β Gene-511 C>T Polymorphism

Are Polyphenols Strong Dietary Agents Against Neurotoxicity and Neurodegeneration?

A Small Molecule Activator of p300/CBP Histone Acetyltransferase Promotes Survival and Neurite Growth in a Cellular Model of Parkinson’s Disease

Biochanin A Protects Against Lipopolysaccharide-Induced Damage of Dopaminergic Neurons Both In Vivo and In Vitro via Inhibition of Microglial Activation

Transient Receptor Potential Channels in Microglia: Roles in Physiology and Disease