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Transcriptome analysis of zebrafish models of familial Alzheimer's disease and Sanfilippo syndrome childhood dementia display effects-in-common on the lysosome, oxidative phosphorylation and the ribosome

ABSTRACT: Transcriptome analysis of zebrafish models of familial Alzheimer's disease and Sanfilippo syndrome childhood dementia display effects-in-common on the lysosome, oxidative phosphorylation and the ribosome

PROVIDER: PRJNA1013345 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25917801_1.fastq.gz	Fastqsanger.gz
	SRR25917801_2.fastq.gz	Fastqsanger.gz
	SRR25917802_1.fastq.gz	Fastqsanger.gz
	SRR25917802_2.fastq.gz	Fastqsanger.gz
	SRR25917803_1.fastq.gz	Fastqsanger.gz

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Comparison of the effects of mutaions modelling early-onset familial Alzheimer's disease and Sanfilippo syndrome childhood dementia in zebrafish larvae

Project description:Neural cells are under immense pressure to maintain proper degradation of molecules using their endo-lysosomal pathway (ELP). In Alzheimer’s disease (AD), the gradual cognitive worsening of this age-related disorder is partially due to dysfunction of the ELP. However, AD is a complex disorder and how the genetic landscape eventually leads to AD is unclear. Sanfilippo syndrome childhood dementia (mucopolysaccharidosis type III, MPSIII) is an extreme consequence of ELP dysfunction, where inherited recessive mutations result in the inability to properly catabolise a particular polysaccharide, which ultimately accumulates and interferes with the function of the ELP. Unlike AD, Sanfilippo is genetically simple (all causative genes are identified). The primary biochemical consequences are understood and animal models of Sanfilippo are considered excellent models of the human disease. Since Sanfilippo and AD show similar pathological changes, they likely share disease-associated mechanisms. Here, we dissect the similarity between AD and Sanfilippo using RNA-seq. We have generated zebrafish knock-in models of both diseases: the early-onset familial AD-like (EOfAD-like) mutation psen1 Q96_K97del and the MPSIII-like mutation naglu A603fs. We generated a family of zebrafish containing wild type, heterozygous EOfAD-like and homozygous MPSIII-like genotypes. We raised the family until 7 days post fertilisation and performed mRNA-seq on n = 8 induvial larvae per genotype. A power calculation revealed that this experiment was only contained ~50% power to detect differentially expressed genes. Nevertheless, changes to the expression of genes encoding proteins involved in lysosomal function could be detected in the MPS-III mutant larvae, suggesting a homeostatic response as the cells which make up the larval RNA-seq samples respond to dysfunctional lysosomes.

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