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Restrained Phosphatidylcholine Synthesis in a Cellular Model of Down’s Syndrome is Associated with the Overexpression of Dyrk1A

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Abstract

Aberrant formation of the cerebral cortex could be attributed to the lack of suitable substrates that direct the migration of neurons. Previous work carried out at our laboratory has shown that oleic acid is a neurotrophic factor. In order to characterize the effect of oleic acid in a cellular model of Down’s syndrome (DS), here, we used immortalized cell lines derived from the cortex of trisomy Ts16 and euploid mice. We report that in the plasma membrane of euploid cells, an increase in phosphatidylcholine concentrations occurs in the presence of oleic acid. However, in trisomic cells, oleic acid failed to increase phosphatidylcholine incorporation into the plasma membrane. Gene expression analysis of trisomic cells revealed that the phosphatidylcholine biosynthetic pathway was deregulated. Taken together, these results suggest that the overdose of specific genes in trisomic lines delays differentiation in the presence of oleic acid. The dual-specificity tyrosine (Y) phosphorylation-regulated kinase 1A (DYRK1A) gene is located on human chromosome 21. DYRK1A contributes to intellectual disability and the early onset of Alzheimer’s disease in DS patients. Here, we explored the potential role of Dyrk1A in the reduction of phosphatidylcholine concentrations in trisomic cells in the presence of oleic acid. The downregulation of Dyrk1A by small interfering RNA (siRNA) in trisomic cells returned phosphatidylcholine concentrations up to similar levels to those of euploid cells in the presence of oleic acid. Thus, our results highlight the role of Dyrk1A in brain development through the modulation of phosphatidylcholine location, levels and synthesis.

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Abbreviations

DS:

Down’s syndrome

CNh:

Cerebral cortex cells of euploid mice

CTb:

Cerebral cortex cells of trisomy 16 mice

PC:

Phosphatidylcholine

DYRK1A:

Dual-specificity tyrosine (Y)-regulated kinase

ChAT:

Choline acetyltransferase

BSA:

Bovine serum albumin

DMEM:

Dulbecco’s modified Eagle’s medium

FCS:

Fetal calf serum

PBS:

Phosphate-buffered saline

siRNA:

Small interfering RNA

CKα:

Choline kinase alpha

CCTα:

Choline cytidylyltransferase alpha

CPT:

CDP-choline:1,2-diacylglycerol phosphocholinetransferase

PEMT:

Phosphatidylethanolamine methyltransferase

SAM:

S-Adenosylmethionine

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Acknowledgments

This work was supported by the Ramón Areces Foundation (M.H.) and Samuel Solórzano Foundation, University of Salamanca, Spain (A.V.). We are grateful to C. Raposo for helping with the chromatographic analysis by HPLC carried out at the Mass Spectrometry facilities of the University of Salamanca and to T. del Rey for the technical assistance.

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  1. Departamento de Bioquímica y Biología Molecular, Instituto de Investigación Biomédica de Salamanca (IBSAL), Instituto de Neurociencias de Castilla y León (INCYL), Universidad de Salamanca, Salamanca, Spain

    Maruan Hijazi, José M. Medina & Ana Velasco

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  1. Maruan Hijazi
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  2. José M. Medina
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  3. Ana Velasco
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Correspondence to Ana Velasco.

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Hijazi, M., Medina, J.M. & Velasco, A. Restrained Phosphatidylcholine Synthesis in a Cellular Model of Down’s Syndrome is Associated with the Overexpression of Dyrk1A. Mol Neurobiol 54, 1092–1100 (2017). https://doi.org/10.1007/s12035-016-9728-2

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