Caenorhabditis elegans Models to Investigate the Mechanisms Underlying Tau Toxicity in Tauopathies.

Carmina Natale,Luisa Diomede,Maria Monica Barzago

doi:10.3390/brainsci10110838

Carmina Natale, Luisa Diomede + Show 1 more

Open Access

https://doi.org/10.3390/brainsci10110838

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Abstract

The understanding of the genetic, biochemical, and structural determinants underlying tau aggregation is pivotal in the elucidation of the pathogenic process driving tauopathies and the design of effective therapies. Relevant information on the molecular basis of human neurodegeneration in vivo can be obtained using the nematode Caenorhabditis elegans (C. elegans). To this end, two main approaches can be applied: the overexpression of genes/proteins leading to neuronal dysfunction and death, and studies in which proteins prone to misfolding are exogenously administered to induce a neurotoxic phenotype. Thanks to the easy generation of transgenic strains expressing human disease genes, C. elegans allows the identification of genes and/or proteins specifically associated with pathology and the specific disruptions of cellular processes involved in disease. Several transgenic strains expressing human wild-type or mutated tau have been developed and offer significant information concerning whether transgene expression regulates protein production and aggregation in soluble or insoluble form, onset of the disease, and the degenerative process. C. elegans is able to specifically react to the toxic assemblies of tau, thus developing a neurodegenerative phenotype that, even when exogenously administered, opens up the use of this assay to investigate in vivo the relationship between the tau sequence, its folding, and its proteotoxicity. These approaches can be employed to screen drugs and small molecules that can interact with the biogenesis and dynamics of formation of tau aggregates and to analyze their interactions with other cellular proteins.

Highlights

For many neurodegenerative diseases—including Alzheimer’s disease (AD), progressive supranuclear palsy, Pick’s disease, cortico-basal degeneration, and post-encephalitic parkinsonism—the ability of proteins to change their conformation and generate insoluble deposits in the brain of patients is believed to play a crucial role in etiopathology [1,2,3]
We demonstrated that the administration to worms of light chain (LC) purified from AL patients with compromised cardiac function selectively and permanently impaired the C. elegans pharyngeal function [105]
In the absence of animal models for AL amyloidosis and due to the need to improve the survival of patients, the information obtained in C. elegans has been for the first time directly translated into clinical application supporting the design of clinical studies

Summary

Introduction

For many neurodegenerative diseases—including Alzheimer’s disease (AD), progressive supranuclear palsy, Pick’s disease, cortico-basal degeneration, and post-encephalitic parkinsonism—the ability of proteins to change their conformation and generate insoluble deposits in the brain of patients is believed to play a crucial role in etiopathology [1,2,3]. We generated new transgenic strains expressing human tau in the wild-type (WT) or mutated form whose sequence was deduced from patients suffering from FTLD with different atypical clinical phenotypes and carrying mutations on codon 363 of the MAPT gene. Studies in vitro have indicated that the two substitutions differently affected microtubule polymerization and, unlike other MAPT mutations, resulted in the production of tau with a high propensity to form oligomers [57] These two new C. elegans strains were employed to elucidate whether the expression of the mutant genes resulted in gene-specific disease hallmarks. To this end, their functional and biochemical characteristics were compared to those of transgenic nematodes expressing human 2N4R tau WT. Given that V363A mutation is the most toxic and phosphorylated, this finding points to the key role of soluble tau oligomers in driving the proteotoxic process involved in tauopathy

Other Non-Mammalian Models of Tauopathy

Conclusions

Findings

Amyloid