Author
Listed:
- Björn F. Vahsen
(University of Oxford, John Radcliffe Hospital
University of Oxford, Dorothy Crowfoot Hodgkin Building)
- Sumedha Nalluru
(University of Oxford, John Radcliffe Hospital)
- Georgia R. Morgan
(University of Oxford, John Radcliffe Hospital)
- Lucy Farrimond
(University of Oxford, John Radcliffe Hospital
University of Oxford, Dorothy Crowfoot Hodgkin Building)
- Emily Carroll
(University of Oxford, John Radcliffe Hospital
University of Oxford, Dorothy Crowfoot Hodgkin Building)
- Yinyan Xu
(University of Oxford, John Radcliffe Hospital
University of Oxford, Dorothy Crowfoot Hodgkin Building
University of Oxford)
- Kaitlyn M. L. Cramb
(University of Oxford, Dorothy Crowfoot Hodgkin Building
University of Oxford, Dorothy Crowfoot Hodgkin Building)
- Benazir Amein
(University of Oxford, John Radcliffe Hospital)
- Jakub Scaber
(University of Oxford, John Radcliffe Hospital
University of Oxford, Dorothy Crowfoot Hodgkin Building)
- Antigoni Katsikoudi
(University of Oxford, Dorothy Crowfoot Hodgkin Building
University of Oxford, Dorothy Crowfoot Hodgkin Building)
- Ana Candalija
(University of Oxford, John Radcliffe Hospital)
- Mireia Carcolé
(UK Dementia Research Institute at UCL and Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology)
- Ruxandra Dafinca
(University of Oxford, John Radcliffe Hospital
University of Oxford, Dorothy Crowfoot Hodgkin Building)
- Adrian M. Isaacs
(UK Dementia Research Institute at UCL and Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology)
- Richard Wade-Martins
(University of Oxford, Dorothy Crowfoot Hodgkin Building
University of Oxford, Dorothy Crowfoot Hodgkin Building)
- Elizabeth Gray
(University of Oxford, John Radcliffe Hospital)
- Martin R. Turner
(University of Oxford, John Radcliffe Hospital)
- Sally A. Cowley
(University of Oxford)
- Kevin Talbot
(University of Oxford, John Radcliffe Hospital
University of Oxford, Dorothy Crowfoot Hodgkin Building)
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, with additional pathophysiological involvement of non-neuronal cells such as microglia. The commonest ALS-associated genetic variant is a hexanucleotide repeat expansion (HRE) mutation in C9orf72. Here, we study its consequences for microglial function using human iPSC-derived microglia. By RNA-sequencing, we identify enrichment of pathways associated with immune cell activation and cyto-/chemokines in C9orf72 HRE mutant microglia versus healthy controls, most prominently after LPS priming. Specifically, LPS-primed C9orf72 HRE mutant microglia show consistently increased expression and release of matrix metalloproteinase-9 (MMP9). LPS-primed C9orf72 HRE mutant microglia are toxic to co-cultured healthy motor neurons, which is ameliorated by concomitant application of an MMP9 inhibitor. Finally, we identify release of dipeptidyl peptidase-4 (DPP4) as a marker for MMP9-dependent microglial dysregulation in co-culture. These results demonstrate cellular dysfunction of C9orf72 HRE mutant microglia, and a non-cell-autonomous role in driving C9orf72-ALS pathophysiology in motor neurons through MMP9 signaling.
Suggested Citation
Björn F. Vahsen & Sumedha Nalluru & Georgia R. Morgan & Lucy Farrimond & Emily Carroll & Yinyan Xu & Kaitlyn M. L. Cramb & Benazir Amein & Jakub Scaber & Antigoni Katsikoudi & Ana Candalija & Mireia C, 2023.
"C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9,"
Nature Communications, Nature, vol. 14(1), pages 1-16, December.
Handle:
RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41603-0
DOI: 10.1038/s41467-023-41603-0
Download full text from publisher
References listed on IDEAS
- Madelyn E. McCauley & Jacqueline Gire O’Rourke & Alberto Yáñez & Janet L. Markman & Ritchie Ho & Xinchen Wang & Shuang Chen & Deepti Lall & Mengyao Jin & A. K. M. G. Muhammad & Shaughn Bell & Jesse La, 2020.
"C9orf72 in myeloid cells suppresses STING-induced inflammation,"
Nature, Nature, vol. 585(7823), pages 96-101, September.
Full references (including those not matched with items on IDEAS)
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