Motor cortex transcriptome reveals microglial key events in amyotrophic lateral sclerosis
Por:
Dols-Icardo, O, Montal, V, Sirisi, S, Lopez-Pernas, G, Cervera-Carles, L, Querol-Vilaseca, M, Munoz, L, Belbin, O, Alcolea, D, Molina-Porcel, L, Pegueroles, J, Turon-Sans, J, Blesa, R, Lleo, A, Fortea, J, Rojas-Garcia, R, Clarimon, J
Publicada:
1 sep 2020
Ahead of Print:
15 jul 2020
Resumen:
Objective
To identify transcriptomic changes, neuropathologic correlates, and cellular subpopulations in the motor cortex of sporadic amyotrophic lateral sclerosis (ALS).
Methods
We performed massive RNA sequencing of the motor cortex of patients with ALS (n = 11) and healthy controls (HCs; n = 8) and analyzed gene expression alterations, differential isoform usage, and gene coexpression networks. Furthermore, we used cell type deconvolution algorithms with human single-nucleus RNA sequencing data as reference to identify perturbations in cell type composition associated with ALS. We performed immunohistochemical techniques to evaluate neuropathologic changes in this brain region.
Results
We report extensive RNA expression alterations at gene and isoform levels, characterized by the enrichment of neuroinflammatory and synaptic-related pathways. The assembly of gene coexpression modules confirmed the involvement of these 2 major transcriptomic changes, which also showed opposite directions related to the disease. Cell type deconvolution revealed an overrepresentation of microglial cells in ALS compared with HC. Notably, microgliosis was driven by a subcellular population presenting a gene expression signature overlapping with the recently described disease-associated microglia (DAM). Using immunohistochemistry, we further evidenced that this microglial subpopulation is overrepresented in ALS and that the density of pTDP43 aggregates negatively correlates with the proportion of microglial cells.
Conclusions
DAM has a central role in microglia-related neuroinflammatory changes in the motor cortex of patients with ALS, and these alterations are coupled with a reduced expression of postsynaptic transcripts.
Filiaciones:
Dols-Icardo, O:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Dept Neurol, Barcelona, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, Barcelona, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Montal, V:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Dept Neurol, Barcelona, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, Barcelona, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Sirisi, S:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Dept Neurol, Barcelona, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, Barcelona, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Lopez-Pernas, G:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Dept Neurol, Barcelona, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, Barcelona, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Cervera-Carles, L:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Dept Neurol, Barcelona, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, Barcelona, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Querol-Vilaseca, M:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Dept Neurol, Barcelona, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, Barcelona, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Munoz, L:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Dept Neurol, Barcelona, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, Barcelona, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Belbin, O:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Dept Neurol, Barcelona, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, Barcelona, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Alcolea, D:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Dept Neurol, Barcelona, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, Barcelona, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Molina-Porcel, L:
Hosp Clin Barcelona, Neurol Tissue Bank Biobanc, IDIBAPS, Barcelona, Spain
Univ Barcelona, Hosp Clin, Dept Neurol, Alzheimers Dis & Other Cognit Disorders Unit,Inst, Barcelona, Spain
Pegueroles, J:
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Turon-Sans, J:
Network Ctr Biomed Res Rare Dis CIBERER, Madrid, Spain
Univ Autonoma Barcelona, Dept Neurol, Neuromuscular Disorders Unit, Hosp Santa Creu & St Pau, Barcelona, Spain
Blesa, R:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Dept Neurol, Barcelona, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, Barcelona, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Lleo, A:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Dept Neurol, Barcelona, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, Barcelona, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Fortea, J:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Dept Neurol, Barcelona, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, Barcelona, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Rojas-Garcia, R:
Network Ctr Biomed Res Rare Dis CIBERER, Madrid, Spain
Univ Autonoma Barcelona, Dept Neurol, Neuromuscular Disorders Unit, Hosp Santa Creu & St Pau, Barcelona, Spain
Clarimon, J:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Dept Neurol, Barcelona, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, Barcelona, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Gold, Green Published
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