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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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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.

2022-11-08 | GSE217196 | GEO

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

Project description:Here, we use intra-family analysis to compare the gene expression profiles of one of our zebrafish models of EOfAD; psen1Q96_K97del) and our model of Sanfilippo syndrome (MPS IIIB, nagluA603fs ) in young adult brains (6 months of age). We identified distinct changes to gene expression in each model at both ages. However, important commonalities were also observed, pointing to fundamental, underlying similarities in pathological mechanisms. Our findings highlight the potential of zebrafish models as valuable tools for investigation of neurodegenerative diseases.

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

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Reduction of Nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43-related neurodegeneration

Project description:Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in TARDBP, encoding TDP-43, account for less than 1% of all ALS cases, TDP-43-positive aggregates are present in nearly all ALS patients, including patients with sporadic ALS (sALS) or carrying other familial ALS (fALS)-causing mutations. Interestingly, TDP-43 inclusions are also present in subsets of patients with frontotemporal dementia, Alzheimer’s disease, and Parkinson’s disease; therefore, methods of activating intracellular protein quality control machinery capable of clearing toxic cytoplasmic TDP-43 species may alleviate disease-related phenotypes. Here, we identify a novel function of Nemo-like kinase (Nlk) as a negative regulator of lysosome biogenesis. Genetic or pharmacological reduction of Nlk increased lysosome formation and improved clearance of aggregated TDP-43. Furthermore, Nlk reduction ameliorated pathological, behavioral, and lifespan deficits in two distinct mouse models of TDP-43 proteinopathy. Because many toxic proteins can be cleared along the autophagy-lysosome axis, targeted reduction of Nlk represents a potential approach to therapy development for multiple neurodegenerative disorders.

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Targeted sequencing of patients affected by familial or sporadic Alzheimer's disease

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LSD1 inhibition induces neurodegeneration and provides a common link to Alzheimer's disease and Frontotemporal dementia

Project description:Alzheimer’s disease (AD) and Frontotemporal dementia (FTD) are the two most common forms of dementia that occur during aging. Both AD and FTD are associated with the pathological aggregation of proteins. Nevertheless, it remains unclear how these protein aggregates lead to neuronal cell death in these dementias. Here we show that the histone demethylase LSD1 is mislocalized with cytoplasmic aggregates in human cases of AD and FTD. In addition, loss of LSD1 systemically in adult mice is sufficient to recapitulate many aspects of these diseases. From these data, we propose that the aggregation of Tau and TDP-43 lead to neuronal cell death in AD and FTD by interfering with the continuous requirement for LSD1 to repress inappropriate transcription. Furthermore, we observe the inappropriate reactivation of stem cell loci in the hippocampal neurons of LSD1 mutant mice. This suggests that LSD1 may function to maintain the fate of differentiated neurons by repressing stem cell transcription.

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