The transcriptomic landscape of neurons carrying PSEN1 mutations reveals changes in extracellular matrix components and non-coding gene expression
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The transcriptomic landscape of neurons carrying PSEN1 mutations reveals changes in extracellular matrix components and non-coding gene expression. / Corsi, Giulia I.; Gadekar, Veerendra P.; Haukedal, Henriette; Doncheva, Nadezhda T.; Anthon, Christian; Ambardar, Sheetal; Palakodeti, Dasaradhi; Hyttel, Poul; Freude, Kristine; Seemann, Stefan E.; Gorodkin, Jan.
In: Neurobiology of Disease, Vol. 178, 105980, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - The transcriptomic landscape of neurons carrying PSEN1 mutations reveals changes in extracellular matrix components and non-coding gene expression
AU - Corsi, Giulia I.
AU - Gadekar, Veerendra P.
AU - Haukedal, Henriette
AU - Doncheva, Nadezhda T.
AU - Anthon, Christian
AU - Ambardar, Sheetal
AU - Palakodeti, Dasaradhi
AU - Hyttel, Poul
AU - Freude, Kristine
AU - Seemann, Stefan E.
AU - Gorodkin, Jan
N1 - Funding Information: This work was supported by the Innovation Fund Denmark [ 4108-00008B, 4096-00001B ] and the Novo Nordisk Foundation [ NNF14CC0001 , NNF21OC0071571 ]. Publisher Copyright: © 2022
PY - 2023
Y1 - 2023
N2 - Alzheimer's disease (AD) is a progressive and irreversible brain disorder, which can occur either sporadically, due to a complex combination of environmental, genetic, and epigenetic factors, or because of rare genetic variants in specific genes (familial AD, or fAD). A key hallmark of AD is the accumulation of amyloid beta (Aβ) and Tau hyperphosphorylated tangles in the brain, but the underlying pathomechanisms and interdependencies remain poorly understood. Here, we identify and characterise gene expression changes related to two fAD mutations (A79V and L150P) in the Presenilin-1 (PSEN1) gene. We do this by comparing the transcriptomes of glutamatergic forebrain neurons derived from fAD-mutant human induced pluripotent stem cells (hiPSCs) and their individual isogenic controls generated via precision CRISPR/Cas9 genome editing. Our analysis of Poly(A) RNA-seq data detects 1111 differentially expressed coding and non-coding genes significantly altered in fAD. Functional characterisation and pathway analysis of these genes reveal profound expression changes in constituents of the extracellular matrix, important to maintain the morphology, structural integrity, and plasticity of neurons, and in genes involved in calcium homeostasis and mitochondrial oxidative stress. Furthermore, by analysing total RNA-seq data we reveal that 30 out of 31 differentially expressed circular RNA genes are significantly upregulated in the fAD lines, and that these may contribute to the observed protein-coding gene expression changes. The results presented in this study contribute to a better understanding of the cellular mechanisms impacted in AD neurons, ultimately leading to neuronal damage and death.
AB - Alzheimer's disease (AD) is a progressive and irreversible brain disorder, which can occur either sporadically, due to a complex combination of environmental, genetic, and epigenetic factors, or because of rare genetic variants in specific genes (familial AD, or fAD). A key hallmark of AD is the accumulation of amyloid beta (Aβ) and Tau hyperphosphorylated tangles in the brain, but the underlying pathomechanisms and interdependencies remain poorly understood. Here, we identify and characterise gene expression changes related to two fAD mutations (A79V and L150P) in the Presenilin-1 (PSEN1) gene. We do this by comparing the transcriptomes of glutamatergic forebrain neurons derived from fAD-mutant human induced pluripotent stem cells (hiPSCs) and their individual isogenic controls generated via precision CRISPR/Cas9 genome editing. Our analysis of Poly(A) RNA-seq data detects 1111 differentially expressed coding and non-coding genes significantly altered in fAD. Functional characterisation and pathway analysis of these genes reveal profound expression changes in constituents of the extracellular matrix, important to maintain the morphology, structural integrity, and plasticity of neurons, and in genes involved in calcium homeostasis and mitochondrial oxidative stress. Furthermore, by analysing total RNA-seq data we reveal that 30 out of 31 differentially expressed circular RNA genes are significantly upregulated in the fAD lines, and that these may contribute to the observed protein-coding gene expression changes. The results presented in this study contribute to a better understanding of the cellular mechanisms impacted in AD neurons, ultimately leading to neuronal damage and death.
KW - Alzheimer's disease
KW - Circular RNAs
KW - cis-regulation
KW - CRISPR/Cas9
KW - Extracellular matrix
KW - Glutamatergic forebrain neurons
KW - hiPSCs
KW - Long non-coding RNAs
KW - Presenilin-1
KW - RNA-seq
U2 - 10.1016/j.nbd.2022.105980
DO - 10.1016/j.nbd.2022.105980
M3 - Journal article
C2 - 36572121
AN - SCOPUS:85146629565
VL - 178
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
M1 - 105980
ER -
ID: 334714016