Astrocyte dysfunction and neuronal network hyperactivity in a CRISPR engineered pluripotent stem cell model of frontotemporal dementia
(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
(Less)
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.
- author
- organization
-
- Glial and Neuronal Biology (research group)
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- Stem Cells, Aging and Neurodegeneration (research group)
- Developmental and Regenerative Neurobiology (research group)
- Experimental Epilepsy Group (research group)
- LUCC: Lund University Cancer Centre
- Hematopoietic Stem Cell Development (research group)
- MultiPark: Multidisciplinary research focused on Parkinson´s disease
- Regenerative Neurophysiology (research group)
- Behavioural Neuroscience Laboratory (research group)
- publishing date
- 2023
- 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}}, }