Abstract
Tauopathy refers to a group of progressive neurodegenerative diseases, including frontotemporal lobar degeneration and Alzheimer’s disease, which correlate with the malfunction of microtubule-associated protein Tau (MAPT) due to abnormal hyperphosphorylation, leading to the formation of intracellular aggregates in the brain. Despite extensive efforts to understand tauopathy and develop an efficient therapy, our knowledge is still far from complete. To find a solution for this group of devastating diseases, several animal models that mimic diverse disease phenotypes of tauopathy have been developed. Rodents are the dominating tauopathy models because of their similarity to humans and established disease lines, as well as experimental approaches. However, powerful genetic animal models using Drosophila, zebrafish, and C. elegans have also been developed for modeling tauopathy and have contributed to understanding the pathophysiology of tauopathy. The success of these models stems from the short lifespans, versatile genetic tools, real-time in-vivo imaging, low maintenance costs, and the capability for high-throughput screening. In this review, we summarize the main findings on mechanisms of tauopathy and discuss the current tauopathy models of these non-rodent genetic animals, highlighting their key advantages and limitations in tauopathy research.
Highlights
We focus on Drosophila, zebrafish, and C. elegans, highlighting their advantages and limitations as tauopathy models in order to unveil mechanistic aspects of tauopathy and to develop novel therapeutic strategies
3 and exon 10 are subject to alternative splicing. 0N, 1N, or 2N isoform depends on the presence of exon 2 and 3, while 3R or 4R isoform is determined by the presence of exon 10. (B) Mutations of the microtubule-associated protein Tau (MAPT) gene used to generate tauopathy models in Drosophila, zebrafish and C. elegans. dark orange, Calpain-resistant mutations; red, reduced microtubule-binding and increased aggregation mutations; green, a reduced microtubule-binding and increased oligomerization, but not fibrillization mutation; pink, an increased phosphorylation mutation; blue, anti-aggregation mutations; grey, promote microtubule assembly and increased oligomerization, but not fibrillization mutation; black, increased disease-associated lysine acetylation mutations; italic black, phosphorylation-incompetent mutations
TauWT C. elegans model, suppression of this gene either by RNAi or inhibitor resulted in increased whole-body glucose levels and Tau phosphorylation, consistent with the observation in Alzheimer’s Disease (AD) patients [245], suggesting that the disturbance in energy metabolism can significantly induce the neurotoxicity of pathological Tau [246]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Tauopathy refers to a group of neurodegenerative disorders that share a common feature of neurofibrillary tangles (NFT) originating from the aggregation of abnormal hyperphosphorylated and paired helical filament (PHF) Tau proteins [1]. Tau protein is subject to diverse post-translational modifications (PTMs), including glycosylation, glycation, nitration, polyamination, phosphorylation, ubiquitination, oxidation, cleavage or truncation, small ubiquitin-like modifier (SUMO) modification, and aggregation [12]. 19 Tau-targeting therapeutic compounds have been proposed and tested based on diverse mechanisms by which Tau protein aggregation causes neurodegeneration. We first summarize underlying mechanisms of tauopathy and discuss research on tauopathy using non-rodent genetic animal models. The most popular tauopathy model, the rodent model, has been extensively reviewed elsewhere [14] and is not covered here
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