Inhibition of tau aggregation in a novel Caenorhabditis elegans model of tauopathy mitigates proteotoxicity

Institute of Biology III, University of Freiburg, 79104 Freiburg, Germany.
Human Molecular Genetics (Impact Factor: 6.39). 05/2012; 21(16):3587-603. DOI: 10.1093/hmg/dds190
Source: PubMed


Increased Tau protein amyloidogenicity has been causatively implicated in several neurodegenerative diseases, collectively called tauopathies. In pathological conditions, Tau becomes hyperphosphorylated and forms intracellular aggregates. The deletion of K280, which is a mutation that commonly appears in patients with frontotemporal dementia with Parkinsonism linked to chromosome 17, enhances Tau aggregation propensity (pro-aggregation). In contrast, introduction of the I277P and I308P mutations prevents β-sheet formation and subsequent aggregation (anti-aggregation). In this study, we created a tauopathy model by expressing pro- or anti-aggregant Tau species in the nervous system of Caenorhabditis elegans. Animals expressing the highly amyloidogenic Tau species showed accelerated Tau aggregation and pathology manifested by severely impaired motility and evident neuronal dysfunction. In addition, we observed that the axonal transport of mitochondria was perturbed in these animals. Control animals expressing the anti-aggregant combination had rather mild phenotype. We subsequently tested several Tau aggregation inhibitor compounds and observed a mitigation of Tau proteotoxicity. In particular, a novel compound that crosses the blood-brain barrier of mammals proved effective in ameliorating the motility as well as delaying the accumulation of neuronal defects. Our study establishes a new C. elegans model of Tau aggregation-mediated toxicity and supports the emerging notion that inhibiting the nucleation of Tau aggregation can be neuroprotective.

Download full-text


Available from: Jeelani Pir
  • Source
    • "However, whether or not tau polymerization is directly neurotoxic continues to be a major question (for review, see [1]). Previous studies have established a cell culture, C. elegans, and mouse model of tau aggregation through expression of a tau fragment comprising only the microtubule binding domain with deletion of lysine 280 (K18ΔK280), which has a high propensity for β-structure and aggregation [50-53]. Studies show that expression of K18ΔK280 tau is more lethal than the same fragment without the deletion of lysine 280 (K18), and causes cell death prior to the formation of mature aggregations [50,54,55]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Hirano bodies are actin-rich paracrystalline inclusions found in brains of patients with Alzheimer’s disease (AD), frontotemporal dementia (FTD), and in normal aged individuals. Although studies of post-mortem brain tissue provide clues of etiology, the physiological function of Hirano bodies remains unknown. A cell culture model was utilized to study the interactions of mutant tau proteins, model Hirano bodies, and GSK3β in human astrocytoma cells. Results Most tau variants showed co-localization with model Hirano bodies. Cosedimentation assays revealed this interaction may be direct, as recombinant purified forms of tau are all capable of binding F-actin. Model Hirano bodies had no effect or enhanced cell death induced by tau in the absence of amyloid precursor protein intracellular domain (AICD). In the presence of AICD and tau, synergistic cell death was observed in most cases, and model Hirano bodies decreased this synergistic cell death, except for forms of tau that caused significant cell death in the presence of Hirano bodies only. A role for the kinase GSK3β is suggested by the finding that a dominant negative form of GSK3β reduces this synergistic cell death. A subset of Hirano bodies in brain tissue of both Alzheimer’s disease and normal aged individuals was found to contain tau, with some Hirano bodies in Alzheimer’s disease brains containing hyperphosphorylated tau. Conclusion The results demonstrate a complex interaction between tau and AICD involving activation of GSK3β in promoting cell death, and the ability of Hirano bodies to modulate this process.
    Full-text · Article · Jun 2014 · BMC Neuroscience
  • Source
    • "Several studies using such transgenic animals have led to the important discovery that genes that prolong lifespan also restore proteostasis (protein homeostasis), providing a link between aging and proteotoxicity and thus a plausible reason for the age-dependent onset of neurodegenerative diseases (Morley et al., 2002; Hsu et al., 2003; Morley and Morimoto, 2004; Cohen et al., 2006). Furthermore, C. elegans has been successfully used for the discovery and evaluation of drugs (Calamini et al., 2011; Fatouros et al., 2012; Lublin and Link, 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Caenorhabditis elegans has a number of distinct advantages that are useful for understanding the basis for cellular and organismal dysfunction underlying age-associated diseases of protein misfolding. Although protein aggregation, a key feature of human neurodegenerative diseases, has been typically explored in vivo at the single-cell level using cells in culture, there is now increasing evidence that proteotoxicity has a non-cell-autonomous component and is communicated between cells and tissues in a multicellular organism. These discoveries have opened up new avenues for the use of C. elegans as an ideal animal model system to study non-cell-autonomous proteotoxicity, prion-like propagation of aggregation-prone proteins, and the organismal regulation of stress responses and proteostasis. This Review focuses on recent evidence that C. elegans has mechanisms to transmit certain classes of toxic proteins between tissues and a complex stress response that integrates and coordinates signals from single cells and tissues across the organism. These findings emphasize the potential of C. elegans to provide insights into non-cell-autonomous proteotoxic mechanisms underlying age-related protein-misfolding diseases.
    Full-text · Article · Jan 2014 · Disease Models and Mechanisms
  • Source
    • "mec-7::human tau Touch response defect Human HSP70 protected against mutant tau toxicity. rab-3::human tau Neuronal dysfunction A compound (cmp16) effectively ameliorated the neuronal defects (Fatouros et al., 2012). PD SNCA dat-1::human α-synuclein No obvious defect Dopamine neuron degeneration by expression of human α-synuclein specific in dopamine neuron (Lakso et al., 2003). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neurodegenerative diseases which include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington disease (HD), and others are becoming an increasing threat to human health worldwide. The degeneration and death of certain specific groups of neurons is the hallmark of these diseases. Despite the research progress in identification of several disease-related genes, the mechanisms underlying the neurodegeneration in these diseases remain unclear. Given the molecular conservation in neuronal signaling between Caenorhabditis elegans and vertebrates, increasing number of research scientists has used the nematode to study this group of diseases. This review paper will focus on the model system that has been established in Caenorhabditis elegans to investigate the pathogenetic roles of those reported disease-related genes in AD, PD, ALS, HD and others. The progress in Caenorhabditis elegans provides useful information of the genetic interactions and molecular pathways that are critical in the disease process, and may help our better understanding of the disease mechanisms and search for new therapeutics for these devastating diseases.
    Full-text · Article · Oct 2013 · Experimental Neurology
Show more