| Autor: |
Pegah Masrori, Baukje Bijnens, Kristofer Davie, Suresh Kumar Poovathingal, Annet Storm, Nicole Hersmus, Laura Fumagalli, Ludo Van Den Bosch, Mark Fiers, Dietmar Rudolf Thal, Renzo Mancuso, Philip Van Damme |
| Rok vydání: |
2022 |
| Popis: |
SummaryNeuroinflammation is an important hallmark in amyotrophic lateral sclerosis (ALS). Experimental evidence has highlighted a role of microglia in the modulation of motor neuron degeneration. However, the exact contribution of microglia to both sporadic and genetic forms of ALS is still unclear. We generated single nuclei profiles of spinal cord and motor cortex from sporadic andC9orf72ALS patients, as well as controls. We particularly focused on the transcriptomic responses of both microglia and astrocytes. We confirmed thatC9orf72is highly expressed in microglia and shows a diminished expression in carriers of the hexanucleotide repeat expansion (HRE). This resulted in an impaired response to disease, with specific deficits in phagocytic and lysosomal transcriptional pathways. Astrocytes also displayed a dysregulated response inC9orf72ALS patients, remaining in a homeostatic state. This suggests that C9orf72 HRE alters a coordinated glial response, which ultimately would increase the risk for developing ALS. Our results indicate thatC9orf72HRE results in a selective microglial loss-of-function, likely impairing microglial-astrocyte communication and preventing a global glial response. This is relevant as it indicates that sporadic and familial forms of ALS may present a different cellular substrate, which is of great importance for patient stratification and treatment. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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