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C9orf72 deficiency promotes microglial mediated synaptic loss in aging and amyloid accumulation [bulk RNA-seq]

ABSTRACT: C9orf72 deficiency promotes microglial mediated synaptic loss in aging and amyloid accumulation [bulk RNA-seq]

PROVIDER: PRJNA691543 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13417264.fastq.gz	Fastqsanger.gz
	SRR13417265.fastq.gz	Fastqsanger.gz
	SRR13417266.fastq.gz	Fastqsanger.gz
	SRR13417267.fastq.gz	Fastqsanger.gz
	SRR13417268.fastq.gz	Fastqsanger.gz

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C9orf72 deficiency promotes microglial mediated synaptic loss in aging and amyloid accumulation [scRNA-seq]

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C9orf72 deficiency promotes microglial mediated synaptic loss in aging and amyloid accumulation

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C9orf72 is required for proper macrophage and microglial function in mice

Project description:Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Decreased expression of C9orf72 is seen in expansion carriers, suggesting loss of function may play a role in disease. We find that two independent mouse lines lacking the C9orf72 ortholog (3110043O21Rik) in all tissues developed normally and aged without motor neuron disease. Instead, C9orf72 null mice developed progressive splenomegaly and lymphadenopathy with accumulation of engorged macrophage-like cells. C9orf72 expression was highest in myeloid cells, and loss of C9orf72 led to lysosomal accumulation and altered immune responses in macrophages and microglia, with age-related neuroinflammation similar to C9orf72 ALS but not sporadic ALS patient tissue. Thus, C9orf72 is required for normal function of myeloid cells, and altered microglial function may contribute to neurodegeneration in C9orf72 expansion carriers.

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Project description:C9orf72 repeat expansions cause inherited amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) and result in both loss of C9orf72 protein expression and production of potentially toxic RNA and dipeptide repeat proteins. In addition to ALS/FTD, C9orf72 repeat expansions have been reported in a broad array of neurodegenerative syndromes, including Alzheimer's disease. Here we show that C9orf72 deficiency promotes a change in the homeostatic signature in microglia and a transition to an inflammatory state characterized by an enhanced type I IFN signature. Furthermore, C9orf72-depleted microglia trigger age-dependent neuronal defects, in particular enhanced cortical synaptic pruning, leading to altered learning and memory behaviors in mice. Interestingly, C9orf72-deficient microglia promote enhanced synapse loss and neuronal deficits in a mouse model of amyloid accumulation while paradoxically improving plaque clearance. These findings suggest that altered microglial function due to decreased C9orf72 expression directly contributes to neurodegeneration in repeat expansion carriers independent of gain-of-function toxicities.

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