Transcriptomics analysis of a zebrafish model of Combined Saposin Deficiency
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ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE227551 | GEO | 2023/03/18
REPOSITORIES: GEO
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2016-03-31 | E-GEOD-75083 | biostudies-arrayexpress
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Project description:Microglia repair injury and maintain homeostasis in the brain, but whether aberrant microglial activation can contribute to neurodegeneration remains unclear. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive up-regulation of lysosomal and innate immunity genes, increased complement production, and synaptic pruning activity in microglia. During aging, Grn-/- mice show profound accumulation of microglia and preferential elimination of inhibitory synapses in the ventral thalamus, which contribute to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, blocking complement activation by deleting C1qa gene significantly reduces synaptic pruning by Grn-/- microglia, and mitigates neurodegeneration, behavioral phenotypes and premature mortality in Grn-/- mice. These results uncover a previously unrecognized role of progranulin in suppressing microglia activation during aging, and support the idea that blocking complement activation is a promising therapeutic target for neurodegeneration caused by progranulin deficiency.
2016-03-31 | GSE75083 | GEO
Project description:Background: Niemann-Pick type C is a rare autosomal recessive lysosomal storage disorder presenting aggravating neurologic symptoms due degeneration of specific types of CNS neurons. At present, it is not well understood how neurons react to NPC1 deficiency and why some neuronal cell types are more vulnerable than others. Purpose: We took aimed to uncover how a specific type of CNS neuron that can be highly purified reacts to NPC1 deficiency based on changes in gene expression. Methods: Retinal ganglion cells were purified from individual one-week old Balb/c mice homozygous for a mutant NPC1 allele (NPC1m1N) and wildtype littermates (n = 4 mice each genotype) using immunopanning. Total RNA was isolated from acutely isolated neurons and subjected to RNAseq using 4 biological replicates for each genotype. Results: Our analysis revealed a strong downregulation of transcripts known to be decreased in mutant mice including Npc1 and Calb1 thus validating our approach. We observed a strong upregulation of genes for cellular cholesterol accretion and the downregulation of those for cholesterol release. Other changes including downregulation genes involved in the immune response and synaptic components. Conclusions: The observed changes suggest that neurons already at one week of age sense a cholesterol deficit because lipids accumulate in the endosomal-lysosomal system and cannot be redistributed intracellularly. Gene expression analysis by RNAseq in retinal ganglion cells acutely purified from eight-days-old NPC1-deficient mice and wildtype littermates
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