Impaired development of neocortical circuits contributes to the neurological alterations in DYRK1A haploinsufficiency syndrome

Arranz, Juan; Balducci, Elisa, 1981-; Arató, Krisztina, 1981-; Sánchez-Elexpuru, Gentzane; Najas Sales, Sònia, 1985-; Parras, Alberto; Rebollo, Elena; Pijuan, Isabel; Erb, Ionas; Verde, Gaetano; Sahún, Ignasi; Barallobre, María José; Lucas, José J.; Sánchez, Marina P.; de la Luna, Susana; Arbonés de Rafael, Maria Lourdes, 1959-

Impaired development of neocortical circuits contributes to the neurological alterations in DYRK1A haploinsufficiency syndrome

Mostra el registre complet Registre parcial de l'ítem

dc.contributor.author Arranz, Juan
dc.contributor.author Balducci, Elisa, 1981-
dc.contributor.author Arató, Krisztina, 1981-
dc.contributor.author Sánchez-Elexpuru, Gentzane
dc.contributor.author Najas Sales, Sònia, 1985-
dc.contributor.author Parras, Alberto
dc.contributor.author Rebollo, Elena
dc.contributor.author Pijuan, Isabel
dc.contributor.author Erb, Ionas
dc.contributor.author Verde, Gaetano
dc.contributor.author Sahún, Ignasi
dc.contributor.author Barallobre, María José
dc.contributor.author Lucas, José J.
dc.contributor.author Sánchez, Marina P.
dc.contributor.author de la Luna, Susana
dc.contributor.author Arbonés de Rafael, Maria Lourdes, 1959-
dc.date.accessioned 2019-10-01T08:06:07Z
dc.date.available 2019-10-01T08:06:07Z
dc.date.issued 2019
dc.description.abstract Autism spectrum disorders are early onset neurodevelopmental disorders characterized by deficits in social communication and restricted repetitive behaviors, yet they are quite heterogeneous in terms of their genetic basis and phenotypic manifestations. Recently, de novo pathogenic mutations in DYRK1A, a chromosome 21 gene associated to neuropathological traits of Down syndrome, have been identified in patients presenting a recognizable syndrome included in the autism spectrum. These mutations produce DYRK1A kinases with partial or complete absence of the catalytic domain, or they represent missense mutations located within this domain. Here, we undertook an extensive biochemical characterization of the DYRK1A missense mutations reported to date and show that most of them, but not all, result in enzymatically dead DYRK1A proteins. We also show that haploinsufficient Dyrk1a+/- mutant mice mirror the neurological traits associated with the human pathology, such as defective social interactions, stereotypic behaviors and epileptic activity. These mutant mice present altered proportions of excitatory and inhibitory neocortical neurons and synapses. Moreover, we provide evidence that alterations in the production of cortical excitatory neurons are contributing to these defects. Indeed, by the end of the neurogenic period, the expression of developmental regulated genes involved in neuron differentiation and/or activity is altered. Therefore, our data indicate that altered neocortical neurogenesis could critically affect the formation of cortical circuits, thereby contributing to the neuropathological changes in DYRK1A haploinsufficiency syndrome.
dc.description.sponsorship This work was supported by grants from the Spanish Ministry of Economia, Industria y Competitividad (MINECO) (BFU2016-81887-REDT, SAF2013-46676-P and SAF2016-77971-R to M.L.A. and BFU2013-44513 and BFU2016-76141 to S.L.), the Secretariat of Universities and Research-Generalitat de Catalunya (2014SGR674), and the Fundación Alicia Koplowitz (Spain). The group of S.L. acknowledges the support of the MINECO Centro de Excelencia Severo Ochoa Programme and of the CERCA Programme (Generalitat de Catalunya). G.S-E. and M.P.S. acknowledge the support of the National Institute of Neurological Disorders and Stroke of the National Institutes of Health(USA) (P01NS097197) and the Spanish Instituto de Salud Carlos III (ISCIII), (PI13/00865, Fondo Europeo de Desarrollo Regional -FEDER “A way of making Europe”, Spain). M.J.B. is supported by the CIBERER, an initiative of the ISCIII. J.A., E.B. and S.N. were supported by MINECO predoctoral fellowships (AP2012-3064 and BES2011-047472) and G.S-E. by a predoctoral fellowship from the Fundación Conchita Rábago, Spain.
dc.format.mimetype application/pdf
dc.identifier.citation Arranz J, Balducci E, Arató K, Sánchez-Elexpuru G, Najas S, Parras A et al. Impaired development of neocortical circuits contributes to the neurological alterations in DYRK1A haploinsufficiency syndrome. Neurobiol Dis. 2019;127:210-22. DOI: 10.1016/j.nbd.2019.02.022
dc.identifier.doi http://dx.doi.org/10.1016/j.nbd.2019.02.022
dc.identifier.issn 0969-9961
dc.identifier.uri http://hdl.handle.net/10230/42361
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartof Neurobiology of Disease. 2019;127:210-22
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2016-81887
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2013-46676-P
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2016-77971-R
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2013-44513
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2016-76141
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/BY-NC-ND/4.0/
dc.subject.keyword Autism spectrum disorder
dc.subject.keyword Cerebral cortex
dc.subject.keyword DYRK1A mutations
dc.subject.keyword Epilepsy
dc.subject.keyword Neurodevelopment
dc.subject.keyword Transcriptome
dc.title Impaired development of neocortical circuits contributes to the neurological alterations in DYRK1A haploinsufficiency syndrome
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

Col·leccions

Articles (Center for Genomic Regulation (CRG))
Articles (Departament de Medicina i Ciències de la Vida)