Hypoxanthine-guanine phosphoribosyl transferase regulates early developmental programming of dopamine neurons: implications for Lesch-Nyhan disease pathogenesis

Autor: Alvarez-Fischer, Daniel, Castagner, François, Stettler, Olivier, Massiani-Beaudoin, Olivia, Moya, Kenneth, Bouillot, Colette, Oertel, Wolfgang, Lombès, Anne, Faigle, Wolfgang, Joshi, Rajiv L, Hartmann, Andreas, Prochiantz, Alain, Ceballos-Picot, I., Mockel, L., Potier, M.-C., Dauphinot, L., Shirley, L., Torero-Ibad, R., Fuchs, Julia, Jinnah, H.A.
Přispěvatelé: Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie physico-chimique (IBPC (FR_550)), Centre National de la Recherche Scientifique (CNRS), Somnomar, Sleep Research Institute, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Mathématiques de Bordeaux (IMB), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS), Chaire Processus morphogénétiques, Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, UMR7637, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Collège de France (CDF), Collège de France (CdF), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Collège de France (CdF)-PSL Research University (PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS), Collège de France - Chaire Processus morphogénétiques, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife
Jazyk: angličtina
Rok vydání: 2009
Předmět:
Male
Hypoxanthine Phosphoribosyltransferase
Lesch-Nyhan Syndrome
cells
Dopamine
Neurogenesis
[SDV]Life Sciences [q-bio]
genetic processes
Nerve Tissue Proteins
Biology
Cell Line
03 medical and health sciences
Mice
0302 clinical medicine
Genetics
medicine
Animals
Humans
Molecular Biology
Genetics (clinical)
Cells
Cultured
ComputingMilieux_MISCELLANEOUS
030304 developmental biology
Regulation of gene expression
Homeodomain Proteins
Neurons
0303 health sciences
Dopaminergic
nutritional and metabolic diseases
Gene Expression Regulation
Developmental
General Medicine
Articles
Fibroblasts
medicine.disease
Phenotype
engrailed
Cell biology
enzymes and coenzymes (carbohydrates)
medicine.anatomical_structure
Hypoxanthine-guanine phosphoribosyltransferase
Dopaminergic pathways
Lesch–Nyhan syndrome
030217 neurology & neurosurgery
Zdroj: Human Molecular Genetics
Human Molecular Genetics, Oxford University Press (OUP), 2009, 18 (13), pp.2317-2327. ⟨10.1093/hmg/ddp164⟩
Journal of Inherited Metabolic Disease
Journal of Inherited Metabolic Disease, Springer Verlag, 2010, 33 (S1), pp.S175. ⟨10.1093/hmg/ddp164⟩
ResearcherID
Human Molecular Genetics, 2009, 18 (13), pp.2317-2327. ⟨10.1093/hmg/ddp164⟩
ISSN: 0964-6906
1460-2083
0141-8955
1573-2665
DOI: 10.1093/hmg/ddp164⟩
Popis: Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency results in Lesch-Nyhan disease (LND), where affected individuals exhibit a characteristic neurobehavioral disorder that has been linked with dysfunction of dopaminergic pathways of the basal ganglia. Since the functions of HPRT, a housekeeping enzyme responsible for recycling purines, have no direct relationships with the dopaminergic pathways, the mechanisms whereby HPRT deficiency affect them remain unknown. The current studies demonstrate that HPRT deficiency influences early developmental processes controlling the dopaminergic phenotype, using several different cell models for HPRT deficiency. Microarray methods and quantitative PCR were applied to 10 different HPRT-deficient (HPRT(-)) sublines derived from the MN9D cell line. Despite the variation inherent in such mutant sublines, several consistent abnormalities were evident. Most notable were increases in the mRNAs for engrailed 1 and 2, transcription factors known to play a key role in the specification and survival of dopamine neurons. The increases in mRNAs were accompanied by increases in engrailed proteins, and restoration of HPRT reverted engrailed expression towards normal levels, demonstrating a functional relationship between HPRT and engrailed. The functional relevance of the abnormal developmental molecular signature of the HPRT(-) MN9D cells was evident in impoverished neurite outgrowth when the cells were forced to differentiate chemically. To verify that these abnormalities were not idiosyncratic to the MN9D line, HPRT(-) sublines from the SK-N-BE(2) M17 human neuroblastoma line were evaluated and an increased expression of engrailed mRNAs was also seen. Over-expression of engrailed occurred even in primary fibroblasts from patients with LND in a manner that suggested a correlation with disease severity. These results provide novel evidence that HPRT deficiency may affect dopaminergic neurons by influencing early developmental mechanisms.
Databáze: OpenAIRE
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