Format

Send to

Choose Destination
Cell Death Dis. 2014 Jun 12;5:e1289. doi: 10.1038/cddis.2014.253.

DYRK1A promotes dopaminergic neuron survival in the developing brain and in a mouse model of Parkinson's disease.

Author information

1
Department of Developmental Biology, Instituto de Biología Molecular de Barcelona, CSIC, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
2
Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute and Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain.
3
Unité de Biologie Fonctionnelle et Adaptative, EAC4413 CNRS, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
4
1] Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute and Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain [2] Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona (UAB), Barcelona, Spain [3] Catalan Institute for Research and Advanced Studies (ICREA), Barcelona, Spain.

Abstract

In the brain, programmed cell death (PCD) serves to adjust the numbers of the different types of neurons during development, and its pathological reactivation in the adult leads to neurodegeneration. Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) is a pleiotropic kinase involved in neural proliferation and cell death, and its role during brain growth is evolutionarily conserved. Human DYRK1A lies in the Down syndrome critical region on chromosome 21, and heterozygous mutations in the gene cause microcephaly and neurological dysfunction. The mouse model for DYRK1A haploinsufficiency (the Dyrk1a(+/-) mouse) presents neuronal deficits in specific regions of the adult brain, including the substantia nigra (SN), although the mechanisms underlying these pathogenic effects remain unclear. Here we study the effect of DYRK1A copy number variation on dopaminergic cell homeostasis. We show that mesencephalic DA (mDA) neurons are generated in the embryo at normal rates in the Dyrk1a haploinsufficient model and in a model (the mBACtgDyrk1a mouse) that carries three copies of Dyrk1a. We also show that the number of mDA cells diminishes in postnatal Dyrk1a(+/-) mice and increases in mBACtgDyrk1a mice due to an abnormal activity of the mitochondrial caspase9 (Casp9)-dependent apoptotic pathway during the main wave of PCD that affects these neurons. In addition, we show that the cell death induced by 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), a toxin that activates Casp9-dependent apoptosis in mDA neurons, is attenuated in adult mBACtgDyrk1a mice, leading to an increased survival of SN DA neurons 21 days after MPTP intoxication. Finally, we present data indicating that Dyrk1a phosphorylation of Casp9 at the Thr125 residue is the mechanism by which this kinase hinders both physiological and pathological PCD in mDA neurons. These data provide new insight into the mechanisms that control cell death in brain DA neurons and they show that deregulation of developmental apoptosis may contribute to the phenotype of patients with imbalanced DYRK1A gene dosage.

PMID:
24922073
PMCID:
PMC4611726
DOI:
10.1038/cddis.2014.253
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center