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Astrocyte dysfunction and neuronal network hyperactivity in a CRISPR engineered pluripotent stem cell model of frontotemporal dementia

Canals, Isaac LU ; Comella-Bolla, Andrea LU ; Cepeda-Prado, Efrain LU ; Avaliani, Natalia LU ; Crowe, James A LU orcid ; Oburoglu, Leal LU orcid ; Bruzelius, Andreas LU ; King, Naomi LU ; Pajares, María A and Pérez-Sala, Dolores , et al. (2023) In Brain Communications 5(3). p.1-16
Abstract

Frontotemporal dementia (FTD) is the second most prevalent type of early-onset dementia and up to 40% of cases are familial forms. One of the genes mutated in patients is
CHMP2B, which encodes a protein found in a complex important for maturation of late endosomes, an essential process for recycling membrane proteins through the endolysosomal system. Here, we have generated a
CHMP2B-mutated human embryonic stem cell line using genome editing with the purpose to create a human
in vitro FTD disease model. To date, most studies have focused on neuronal alterations; however, we present a new co-culture system in which neurons and astrocytes are independently generated from human embryonic stem cells and combined in... (More)

Frontotemporal dementia (FTD) is the second most prevalent type of early-onset dementia and up to 40% of cases are familial forms. One of the genes mutated in patients is
CHMP2B, which encodes a protein found in a complex important for maturation of late endosomes, an essential process for recycling membrane proteins through the endolysosomal system. Here, we have generated a
CHMP2B-mutated human embryonic stem cell line using genome editing with the purpose to create a human
in vitro FTD disease model. To date, most studies have focused on neuronal alterations; however, we present a new co-culture system in which neurons and astrocytes are independently generated from human embryonic stem cells and combined in co-cultures. With this approach, we have identified alterations in the endolysosomal system of FTD astrocytes, a higher capacity of astrocytes to uptake and respond to glutamate, and a neuronal network hyperactivity as well as excessive synchronization. Overall, our data indicates that astrocyte alterations precede neuronal impairments and could potentially trigger neuronal network changes, indicating the important and specific role of astrocytes in disease development.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Brain Communications
volume
5
issue
3
article number
fcad158
pages
1 - 16
publisher
Oxford University Press
external identifiers
  • scopus:85163062069
  • pmid:37274831
ISSN
2632-1297
DOI
10.1093/braincomms/fcad158
language
English
LU publication?
yes
additional info
© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.
id
2d6e326f-e875-4f33-b766-e9952759037f
date added to LUP
2023-08-19 22:03:30
date last changed
2024-04-20 02:04:36
@article{2d6e326f-e875-4f33-b766-e9952759037f,
  abstract     = {{<p>Frontotemporal dementia (FTD) is the second most prevalent type of early-onset dementia and up to 40% of cases are familial forms. One of the genes mutated in patients is <br>
 CHMP2B, which encodes a protein found in a complex important for maturation of late endosomes, an essential process for recycling membrane proteins through the endolysosomal system. Here, we have generated a<br>
 CHMP2B-mutated human embryonic stem cell line using genome editing with the purpose to create a human <br>
 in vitro FTD disease model. To date, most studies have focused on neuronal alterations; however, we present a new co-culture system in which neurons and astrocytes are independently generated from human embryonic stem cells and combined in co-cultures. With this approach, we have identified alterations in the endolysosomal system of FTD astrocytes, a higher capacity of astrocytes to uptake and respond to glutamate, and a neuronal network hyperactivity as well as excessive synchronization. Overall, our data indicates that astrocyte alterations precede neuronal impairments and could potentially trigger neuronal network changes, indicating the important and specific role of astrocytes in disease development.<br>
 </p>}},
  author       = {{Canals, Isaac and Comella-Bolla, Andrea and Cepeda-Prado, Efrain and Avaliani, Natalia and Crowe, James A and Oburoglu, Leal and Bruzelius, Andreas and King, Naomi and Pajares, María A and Pérez-Sala, Dolores and Heuer, Andreas and Rylander Ottosson, Daniella and Soriano, Jordi and Ahlenius, Henrik}},
  issn         = {{2632-1297}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{1--16}},
  publisher    = {{Oxford University Press}},
  series       = {{Brain Communications}},
  title        = {{Astrocyte dysfunction and neuronal network hyperactivity in a CRISPR engineered pluripotent stem cell model of frontotemporal dementia}},
  url          = {{http://dx.doi.org/10.1093/braincomms/fcad158}},
  doi          = {{10.1093/braincomms/fcad158}},
  volume       = {{5}},
  year         = {{2023}},
}