Accelerated brain aging towards transcriptional inversion in a zebrafish model of familial Alzheimer’s disease

Hin, Nhi; Newman, Morgan; Kaslin, Jan; Douek, Alon M.; Lumsden, Amanda L.; Zhou, Xin‐Fu; Mañucat-Tan, Noralyn B.; Ludington, Alastair J.; Adelson, David L.; Pederson, Stephen; Lardelli, Michael

doi:10.1101/262162

Cited by 8 publications

(11 citation statements)

References 110 publications

(110 reference statements)

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“…We found that large numbers of H3K27ac-defined enhancers were highly sensitive to the mitochondrial dysfunction resulting from rotenone exposure or TFAM KO. Among the TFs highlighted by motif analysis of upregulated H3K27ac peaks, the ZF factors ZNF264 and ZNF711 show a strong genetic association with neurological functions (Hin et al, 2018;van der Werf et al, 2017). AP-1, another enriched TF, reportedly promotes microglial neuroinflammation and DAergic neuron apoptosis in the SNpc (Tiwari and Pal, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…5A). ZF proteins like ZNF264 contributed to the coordinated gene expression changes during brain aging (Hin et al, 2018) and ZNF711 is reportedly associated with mental retardation and cognitive disability (van der Werf et al, 2017). The DM family of TFs such as DMRT1 and DMRT3 were found to be involved in sexual development (Kopp, 2012).…”

Section: Characterization Of Genomic Enhancers Specific To Mitochondrmentioning

confidence: 99%

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Mitochondrial Dysfunction Induces Epigenetic Dysregulation by H3K27 Hyperacetylation to Perturb Active Enhancers in Parkinson’s Disease Models

Huang¹,

Lou

Charli

et al. 2019

Preprint

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Genetic mutations explain only 10-15% of cases of Parkinson's disease (PD), while an overriding environmental component has been implicated in the etiopathogenesis of PD. But regardless of where the underlying triggers for the onset of familial and sporadic PD fall on the gene-environment axis, mitochondrial dysfunction emerges as a common mediator of dopaminergic neuronal degeneration. Herein, we employ a multidisciplinary approach to convincingly demonstrate that neurotoxicant exposure-and genetic mutation-driven mitochondrial dysfunction share a common mechanism of epigenetic dysregulation. Under both scenarios, lysine 27 acetylation of likely variant H3.2 (H3.2K27ac) increased in dopaminergic neuronal models of PD, thereby opening that region to active enhancer activity via H3K27 hyperacetylation. These vulnerable epigenomic loci represent potential transcription factor motifs for PD pathogenesis. We further confirmed the mitochondrial dysfunction induced H3K27ac during neurodegeneration in ex vivo models of PD. Our results reveal an exciting axis of 'exposure/mutation-mitochondrial dysfunction-metabolism-H3K27ac-transcriptome' for PD pathogenesis. Collectively, the novel mechanistic insights presented here interlinks mitochondrial dysfunction to epigenetic transcriptional regulation in dopaminergic degeneration as well as offer potential new epigenetic intervention strategies for PD.

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Section: Discussionmentioning

confidence: 99%

Section: Characterization Of Genomic Enhancers Specific To Mitochondrmentioning

confidence: 99%

Mitochondrial Dysfunction Induces Epigenetic Dysregulation by H3K27 Hyperacetylation to Perturb Active Enhancers in Parkinson’s Disease Models

Huang¹,

Lou

Charli

et al. 2019

Preprint

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“…The mutant allele, Q96_K97del, of psen1 was a byproduct identified during our introduction of the K97fs mutation into psen1 (that models the K115fs mutation of human PSEN2 -see (8) for an explanation).…”

Section: Methodsmentioning

confidence: 99%

“…Genes differentially expressed between wild type and heterozygous mutant sibling fish were identified using moderated t-tests and a false discovery rate (FDR)-adjusted p-value cutoff of 0.05 as previously described (8,12,13). In total, 251 genes were identified as differentially expressed (see Additional File 1).…”

Section: Differentially Expressed Genes (De Genes)mentioning

confidence: 99%

A familial Alzheimer's disease-like mutation in the zebrafish presenilin 1 gene affects brain energy production

Newman

Pederson

et al. 2019

Preprint

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To prevent or ameliorate Alzheimer's disease (AD) we must understand its molecular basis. AD develops over decades but detailed molecular analysis of AD brains is limited to postmortem tissue where the stresses initiating the disease may be obscured by compensatory responses and neurodegenerative processes. Rare, dominant mutations in a small number of genes, but particularly the gene PRESENILIN 1 (PSEN1), drive early onset of familial AD (EOfAD). Numerous transgenic models of AD have been constructed in mouse and other organisms, but transcriptomic analysis of these models has raised serious doubts regarding their representation of the disease state. Since we lack clarity regarding the molecular mechanism(s) underlying AD, we posit that the most valid approach is to model the human EOfAD genetic state as closely as possible. Therefore, we sought to analyse brains from zebrafish heterozygous for a single, EOfAD-like mutation in their PSEN1-orthologous gene, psen1. We previously introduced an EOfAD-like mutation (Q96_K97del) into the endogenous psen1 gene of zebrafish. Here, we analysed transcriptomes of young adult (6-month-old) entire brains from a family of heterozygous mutant and wild type sibling fish. Gene ontology (GO) analysis revealed effects on mitochondria, particularly ATP synthesis, and on ATP-dependent processes including vacuolar acidification.

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“…Zebrafish are a versatile system in which to investigate, at the molecular level, the effects on the brain and other tissues of fAD mutations (29). The ability to generate large families of siblings and then raise these in a near identical environment (the same tank or the same recirculated-water system) can reduce genetic and environmental variability to allow more sensitive detection of mutation-dependent changes.…”

Section: Introductionmentioning

confidence: 99%

The zebrafish orthologue of familial Alzheimer’s disease genePRESENILIN2 is required for normal adult melanotic skin pigmentation

Jiang

Newman

Lardelli

2018

Preprint

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Alzheimer’s disease is the most common form of age-related dementia. At least 15 mutations in the human gene PRESENILIN 2 (PSEN2) have been found to cause familial Alzheimer’s disease (fAD). Zebrafish possess an orthologous gene, psen2, and present opportunities for investigation of PRESENILIN function related to Alzheimer’s disease. The most prevalent and best characterized fAD mutation in PSEN2 is N141I. The equivalent codon in zebrafish psen2 is N140. We used genome editing technology in zebrafish to target generation of mutations to the N140 codon. We isolated two mutations: psen2N140fs, (hereafter “N140fs”), causing truncation of the coding sequence, and psen2T141_L142delinsMISLISV, (hereafter “T141_L142delinsMISLISV”), that deletes the two codons immediately downstream of N140 and replaces them with seven codons coding for amino acid residues MISLISV. Thus, like almost every fAD mutation in the PRESENILIN genes, this latter mutation does not truncate the gene’s open reading frame. Both mutations are homozygous viable although N140fs transcripts are subject to nonsense-mediated decay and lack any possibility of coding for an active γ-secretase enzyme. N140fs homozygous larvae initially show grossly normal melanotic skin pigmentation but subsequently lose this as they grow while retaining pigmentation in the retinal pigmented epithelium. T141_L142delinsMISLISV homozygotes retain faint skin melanotic pigmentation as adults, most likely indicating that the protein encoded by this allele retains weak γ-secretase activity. Null mutations in the human PRESENILIN genes do not cause Alzheimer’s disease so these two mutations may be useful for future investigation of the differential effects of null and fAD-like PRESENILIN mutations on brain aging.Financial Disclosure StatementThis research was supported by grants from the National Health and Medical Research Council of Australia, GNT1061006 and GNT1126422, and by funds from the School of Biological Sciences of the University of Adelaide. HJ is supported by an Adelaide Scholarship International from the University of Adelaide.Conflict of Interest StatementThe authors declare no conflict of interest.

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Accelerated brain aging towards transcriptional inversion in a zebrafish model of familial Alzheimer’s disease

Cited by 8 publications

References 110 publications

Mitochondrial Dysfunction Induces Epigenetic Dysregulation by H3K27 Hyperacetylation to Perturb Active Enhancers in Parkinson’s Disease Models

Mitochondrial Dysfunction Induces Epigenetic Dysregulation by H3K27 Hyperacetylation to Perturb Active Enhancers in Parkinson’s Disease Models

A familial Alzheimer's disease-like mutation in the zebrafish presenilin 1 gene affects brain energy production

The zebrafish orthologue of familial Alzheimer’s disease genePRESENILIN2 is required for normal adult melanotic skin pigmentation

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