title: Inhibition of tau aggregation in a novel Caenorhabditis elegans model of tauopathy mitigates proteotoxicity.
abstract: 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.
authors.affiliation: Institute of Biology III, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Chronis
authors.initials: C
authors.lastname: Fatouros
authors.forename: Ghulam Jeelani
authors.initials: GJ
authors.lastname: Pir
authors.forename: Jacek
authors.initials: J
authors.lastname: Biernat
authors.forename: Sandhya Padmanabhan
authors.initials: SP
authors.lastname: Koushika
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mandelkow
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Mandelkow
authors.forename: Enrico
authors.initials: E
authors.lastname: Schmidt
authors.forename: Ralf
authors.initials: R
authors.lastname: Baumeister
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001370:Axonal Transport; D001812:Blood-Brain Barrier / Q000187:drug effects; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D008751:Methylene Blue / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010641:Phenotype; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011984:Sensory Receptor Cells / Q000378:metabolism; D024801:Tauopathies / Q000209:etiology* / Q000473:pathology; D013844:Thiazoles / Q000494:pharmacology; D050987:Vesicle-Associated Membrane Protein 1 / Q000378:metabolism; D016875:tau Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C524341:BSc 3094; D029742:Caenorhabditis elegans Proteins; D006834:Hydrazines; D018696:Neuroprotective Agents; D013844:Thiazoles; D050987:Vesicle-Associated Membrane Protein 1; D016875:tau Proteins; D008751:Methylene Blue