Early and Selective Activation and Subsequent Alterations to the Unfolded Protein Response in Down Syndrome Mouse Models

Article type: Research Article

Authors: Lanzillotta, Chiara^{a; b} | Tramutola, Antonella^a | Meier, Shelby^b | Schmitt, Frederick^{b; d; e} | Barone, Eugenio^{a; f} | Perluigi, Marzia^a | Di Domenico, Fabio^{a; 1} | Abisambra, Jose F.^{b; c; d; 1; *}

Affiliations: [a] Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy | [b] Sanders-Brown Center on Aging, College of Medicine, University of Kentucky, Lexington, KY, USA | [c] Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA | [d] Epilepsy Center (EpiC) and Spinal Cord and Brain Injury Research Center (SCoBIRC), College of Medicine, University of Kentucky, Lexington, KY, USA | [e] Department of Neurology, College of Medicine, University of Kentucky, Lexington, KY, USA | [f] Universidad Autónoma de Chile, Instituto de Ciencias Biomédicas, Facultad de alud, Avenida Pedro de Valdivia 425, Providencia, Santiago, Chile

Correspondence: [*] Correspondence to: Jose F. Abisambra, PhD, Sanders-Brown Center on Aging and Department of Physiology, College of Medicine, University of Kentucky, 800 S. Limestone Street, Lexington, KY 40536-0230, USA. E-mail: joe.abisambra@uky.edu.

Note: [1] Co-corresponding authors.

Abstract: Down syndrome (DS) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans, which results from the triplication of chromosome 21. DS individuals have an increased risk of developing Alzheimer’s disease (AD)-like pathology and dementia by the age of 40 due to the triplication of several genes involved in the formation of amyloid plaques and tau tangles. Further, DS and AD are characterized by the aberrant accumulation of unfolded/misfolded proteins resulting from over-burdened protein quality control systems. The accumulation of misfolded proteins in the endoplasmic reticulum (ER) triggers a cellular stress response called the unfolded protein response (UPR). Long-term activation of the UPR mediates neuronal dysfunction in AD. We hypothesized that the UPR is impacted in a mouse model of DS. To test this, we performed gene and protein expression analysis of ER stress markers in the Ts65Dn mouse model of DS at 3, 9, and 18 months. We identified activation of the PERK pathway in Ts65Dn DS mice at 3 months of age compared to euploid controls. We also determined that the early and overt UPR activation decreased with age, the UPR signal was significantly reduced by 18 months. Our data suggest that UPR activation in DS mouse models occurs early before consistent brain neurodegeneration and might be an essential contributor to dys-proteostasis.

Keywords: Down syndrome, eif2 alpha, PERK, Ts65Dn, unfolded protein response

DOI: 10.3233/JAD-170617

Journal: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 347-359, 2018