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Conserved gene signatures shared among MAPT mutations reveal defects in calcium signaling

Authors :
Miguel A. Minaya
Sidhartha Mahali
Abhirami K. Iyer
Abdallah M. Eteleeb
Rita Martinez
Guangming Huang
John Budde
Sally Temple
Alissa L. Nana
William W. Seeley
Salvatore Spina
Lea T. Grinberg
Oscar Harari
Celeste M. Karch
Source :
Frontiers in Molecular Biosciences, Vol 10 (2023)
Publication Year :
2023
Publisher :
Frontiers Media S.A., 2023.

Abstract

Introduction: More than 50 mutations in the MAPT gene result in heterogeneous forms of frontotemporal lobar dementia with tau inclusions (FTLD-Tau). However, early pathogenic events that lead to disease and the degree to which they are common across MAPT mutations remain poorly understood. The goal of this study is to determine whether there is a common molecular signature of FTLD-Tau.Methods: We analyzed genes differentially expressed in induced pluripotent stem cell–derived neurons (iPSC-neurons) that represent the three major categories of MAPT mutations: splicing (IVS10 + 16), exon 10 (p.P301L), and C-terminal (p.R406W) compared with isogenic controls. The genes that were commonly differentially expressed in MAPT IVS10 + 16, p.P301L, and p.R406W neurons were enriched in trans-synaptic signaling, neuronal processes, and lysosomal function. Many of these pathways are sensitive to disruptions in calcium homeostasis. One gene, CALB1, was significantly reduced across the three MAPT mutant iPSC-neurons and in a mouse model of tau accumulation. We observed a significant reduction in calcium levels in MAPT mutant neurons compared with isogenic controls, pointing to a functional consequence of this disrupted gene expression. Finally, a subset of genes commonly differentially expressed across MAPT mutations were also dysregulated in brains from MAPT mutation carriers and to a lesser extent in brains from sporadic Alzheimer disease and progressive supranuclear palsy, suggesting that molecular signatures relevant to genetic and sporadic forms of tauopathy are captured in a dish. The results from this study demonstrate that iPSC-neurons capture molecular processes that occur in human brains and can be used to pinpoint common molecular pathways involving synaptic and lysosomal function and neuronal development, which may be regulated by disruptions in calcium homeostasis.

Details

Language :
English
ISSN :
2296889X
Volume :
10
Database :
Directory of Open Access Journals
Journal :
Frontiers in Molecular Biosciences
Publication Type :
Academic Journal
Accession number :
edsdoj.5c8300a5cf374c2ba727c09cab44b1dd
Document Type :
article
Full Text :
https://doi.org/10.3389/fmolb.2023.1051494