Abstract Details

Title Hexanucleotide repeat expansions in C9orf72 alter microglial responses and prevent a coordinated glial reaction in ALS

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P1 - Poster Session 1 (8:00 AM-9:00 AM)

Poster/Presentation
Number 7-002

Objective Neuroinflammation 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.

Background Single nuclei (sn) RNA sequencing is an interesting approach to study transcriptional changes at the cellular level in human tissues from patients with neurodegenerative disorders. For this study we included motor cortex and spinal cord samples from 5 patients with ALS caused by a C9orf72 hexanucleotide repeat expansion (HRE), from 5 patients with sporadic ALS (mutations in C9orf72, SOD1, TARDBP and FUS excluded) and from 5 control individuals.

Design/Methods We generated single nuclei profiles of spinal cord and motor cortex from sporadic and C9orf72 ALS patients, as well as controls. We particularly focused on the transcriptomic responses of both microglia and astrocytes.

Results We confirmed that C9orf72 is highly expressed in microglia and shows a diminished expression as a result of the HRE. This resulted in an impaired response to disease, with specific deficits in phagocytic and lysosomal transcriptional pathways. Astrocytes also displayed a dysregulated response in C9orf72 ALS patients, remaining in a homeostatic state. This suggesting that C9orf72 HRE alters a coordinated glial response, which ultimately would increase the risk for developing ALS.

Conclusions

Our results indicate that C9orf72 HRE 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 selecting treatments.

Authors/Disclosures
Pegah Masrori, MD (VIB-KU Leuven Center for Brain Research & University Hospital of Leuven) PRESENTER	Dr. Masrori has received research support from European Academy of Neurology.
Baukje Bijnens (Universiteit Antwerpen-CDE)	An immediate family member of Miss Bijnens has received personal compensation in the range of $0-$499 for serving as a Consultant for Lundbeck . The institution of Miss Bijnens has received research support from University of Antwerp .
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Laura Fumagalli (VIB, KULEUVEN)	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Philip Van Damme	The institution of Dr. Van Damme has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for QurAlis. The institution of Dr. Van Damme has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenx. The institution of Dr. Van Damme has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for VectorY. The institution of Dr. Van Damme has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for NRG Therapeutics. The institution of Dr. Van Damme has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. The institution of Dr. Van Damme has received research support from CSL Behring.

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