HGprt deficiency disrupts dopaminergic circuit development in a genetic mouse model of Lesch-Nyhan disease.
HPRT1
Otx2
Radial glia
Sox6
Substantia nigra (SN)
Ventral tegmental area (VTA)
Journal
Cellular and molecular life sciences : CMLS
ISSN: 1420-9071
Titre abrégé: Cell Mol Life Sci
Pays: Switzerland
ID NLM: 9705402
Informations de publication
Date de publication:
04 Jun 2022
04 Jun 2022
Historique:
received:
17
02
2022
accepted:
23
04
2022
revised:
05
04
2022
entrez:
6
6
2022
pubmed:
7
6
2022
medline:
9
6
2022
Statut:
epublish
Résumé
In Lesch-Nyhan disease (LND), deficiency of the purine salvage enzyme hypoxanthine guanine phosphoribosyl transferase (HGprt) leads to a characteristic neurobehavioral phenotype dominated by dystonia, cognitive deficits and incapacitating self-injurious behavior. It has been known for decades that LND is associated with dysfunction of midbrain dopamine neurons, without overt structural brain abnormalities. Emerging post mortem and in vitro evidence supports the hypothesis that the dopaminergic dysfunction in LND is of developmental origin, but specific pathogenic mechanisms have not been revealed. In the current study, HGprt deficiency causes specific neurodevelopmental abnormalities in mice during embryogenesis, particularly affecting proliferation and migration of developing midbrain dopamine (mDA) neurons. In mutant embryos at E14.5, proliferation was increased, accompanied by a decrease in cell cycle exit and the distribution and orientation of dividing cells suggested a premature deviation from their migratory route. An abnormally structured radial glia-like scaffold supporting this mDA neuronal migration might lie at the basis of these abnormalities. Consequently, these abnormalities were associated with an increase in area occupied by TH
Identifiants
pubmed: 35660973
doi: 10.1007/s00018-022-04326-x
pii: 10.1007/s00018-022-04326-x
pmc: PMC9167210
doi:
Substances chimiques
Hypoxanthine Phosphoribosyltransferase
EC 2.4.2.8
Dopamine
VTD58H1Z2X
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
341Subventions
Organisme : NINDS NIH HHS
ID : R01 NS119758
Pays : United States
Organisme : Dutch Research Council
ID : 916.12.167
Pays : Netherlands
Organisme : Dutch Brain Foundation
ID : F2014(1)-16
Organisme : NWO - NWA-ORC
ID : NWA.1160.18.320
Informations de copyright
© 2022. The Author(s).
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