PUBLICATION
The Use of Zebrafish in Transcriptome Analysis of the Early Effects of Mutations Causing Early Onset Familial Alzheimer's Disease and Other Inherited Neurodegenerative Conditions
- Authors
- Lardelli, M., Baer, L., Hin, N., Allen, A., Pederson, S.M., Barthelson, K.
- ID
- ZDB-PUB-231002-95
- Date
- 2023
- Source
- Journal of Alzheimer's disease : JAD 99(s2): S367-S381 (Journal)
- Registered Authors
- Lardelli, Michael
- Keywords
- Alzheimer’s disease, early onset Alzheimer’s disease, gene expression profiling, genetic, models, transcriptome, zebrafish
- MeSH Terms
-
- Alzheimer Disease*/genetics
- Animals
- Animals, Genetically Modified
- Brain/metabolism
- Brain/pathology
- Disease Models, Animal*
- Gene Expression Profiling
- Humans
- Mutation*/genetics
- Neurodegenerative Diseases/genetics
- Presenilin-1/genetics
- Presenilin-2/genetics
- Transcriptome
- Zebrafish*
- Zebrafish Proteins/genetics
- PubMed
- 37742650 Full text @ J. Alzheimers Dis.
Citation
Lardelli, M., Baer, L., Hin, N., Allen, A., Pederson, S.M., Barthelson, K. (2023) The Use of Zebrafish in Transcriptome Analysis of the Early Effects of Mutations Causing Early Onset Familial Alzheimer's Disease and Other Inherited Neurodegenerative Conditions. Journal of Alzheimer's disease : JAD. 99(s2):S367-S381.
Abstract
The degree to which non-human animals can be used to model Alzheimer's disease is a contentious issue, particularly as there is still widespread disagreement regarding the pathogenesis of this neurodegenerative dementia. The currently popular transgenic models are based on artificial expression of genes mutated in early onset forms of familial Alzheimer's disease (EOfAD). Uncertainty regarding the veracity of these models led us to focus on heterozygous, single mutations of endogenous genes (knock-in models) as these most closely resemble the genetic state of humans with EOfAD, and so incorporate the fewest assumptions regarding pathological mechanism. We have generated a number of lines of zebrafish bearing EOfAD-like and non-EOfAD-like mutations in genes equivalent to human PSEN1, PSEN2, and SORL1. To analyze the young adult brain transcriptomes of these mutants, we exploited the ability of zebrafish to produce very large families of simultaneous siblings composed of a variety of genotypes and raised in a uniform environment. This "intra-family" analysis strategy greatly reduced genetic and environmental "noise" thereby allowing detection of subtle changes in gene sets after bulk RNA sequencing of entire brains. Changes to oxidative phosphorylation were predicted for all EOfAD-like mutations in the three genes studied. Here we describe some of the analytical lessons learned in our program combining zebrafish genome editing with transcriptomics to understand the molecular pathologies of neurodegenerative disease.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping