Inhibition of tau aggregation in a novel Caenorhabditis elegans model of tauopathy mitigates proteotoxicity
| Autor: | Enrico Schmidt, Chronis Fatouros, Sandhya P. Koushika, Ghulam Jeelani Pir, Ralf Baumeister, Jacek Biernat, Eckhard Mandelkow, Eva-Maria Mandelkow |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
metabolism [Caenorhabditis elegans Proteins]
pathology [Tauopathies] BSc 3094 Vesicle-Associated Membrane Protein 1 Mitochondrion medicine.disease_cause Axonal Transport Animals Genetically Modified 0302 clinical medicine pathology [Neurons] etiology [Tauopathies] Phosphorylation pharmacology [Methylene Blue] Genetics (clinical) Caenorhabditis elegans Motor Neurons Neurons Genetics 0303 health sciences Mutation pharmacology [Hydrazines] biology genetics [Caenorhabditis elegans Proteins] General Medicine drug effects [Caenorhabditis elegans] metabolism [Caenorhabditis elegans] Mitochondria Cell biology Phenotype Hydrazines Neuroprotective Agents Tauopathies Blood-Brain Barrier metabolism [Neurons] pharmacology [Thiazoles] genetics [Caenorhabditis elegans] Tauopathy Sensory Receptor Cells pathology [Motor Neurons] drug effects [Blood-Brain Barrier] Tau protein Motility metabolism [Vesicle-Associated Membrane Protein 1] tau Proteins Neuroprotection 03 medical and health sciences ddc:570 mental disorders medicine Animals Humans drug effects [Neurons] metabolism [Sensory Receptor Cells] Caenorhabditis elegans Proteins Molecular Biology 030304 developmental biology pharmacology [Neuroprotective Agents] metabolism [Motor Neurons] biology.organism_classification medicine.disease metabolism [Mitochondria] metabolism [tau Proteins] Protein Structure Tertiary Methylene Blue Disease Models Animal genetics [tau Proteins] Thiazoles antagonists & inhibitors [tau Proteins] Proteotoxicity biology.protein 030217 neurology & neurosurgery |
| Zdroj: | Human molecular genetics 21(16), 3587-3603 (2012). doi:10.1093/hmg/dds190 Human Molecular Genetics Human Molecular Genetics; Vol 21 |
| DOI: | 10.1093/hmg/dds190 |
| Popis: | 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 b-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 .A nimals 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. |
| Databáze: | OpenAIRE |
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