No abstract

Neurons from the brains of Alzheimer's disease (AD) and related tauopathy patients contain neurofibrillary tangles composed of hyperphosphorylated tau protein. Tau normally stabilizes microtubules (MTs); however, tau hyperphosphorylation leads to loss of this function with consequent MT destabilization and neuronal dysfunction. Accordingly, MT-stabilizing drugs such as paclitaxel and epothilone D have been shown as possible therapies for AD and related tauopathies. However, MT-stabilizing drugs have common side effects such as neuropathy and neutropenia. To find previously undescribed suppressors of tau-induced MT defects, we established a Drosophila model ectopically expressing human tau in muscle cells, which allow for clear visualization of the MT network. Overexpressed tau was hyperphosphorylated and resulted in decreased MT density and greater fragmentation, consistent with previous reports in AD patients and mouse models. From a genetic screen, we found that a histone deacetylase 6 (HDAC6) null mutation rescued tau-induced MT defects in both muscles and neurons. Genetic and pharmacological inhibition of the tubulin-specific deacetylase activity of HDAC6 indicates that the rescue effect may be mediated by increased MT acetylation. These findings reveal HDAC6 as a unique potential drug target for AD and related tauopathies.disease model | genetic study T au is a neuronal microtubule-associated protein (MAP) that binds to and stabilizes microtubules (MTs). However, in Alzheimer's disease (AD), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), and other tauopathies, tau is hyperphosphorylated and aggregated into straight or paired helical filaments (PHFs) in the cell bodies and neurites of central neurons (1). In vitro biochemical studies demonstrated that hyperphosphorylated tau does not bind to MTs and thus does not promote MT stability (2, 3). Furthermore, mutations in tau lead to FTDP-17, and some of these mutations have been reported to reduce MT-tau binding affinity (4, 5), underscoring the importance of loss of normal MT-stabilizing function of tau in the pathogenesis of neurodegenerative tauopathies.MTs are disrupted in the brains of patients and animal models of tauopathies. For example, MT density was reduced in both hippocampal neurons of transgenic mice expressing V337M mutant human tau and the spinal ventral root axons of transgenic mice expressing the smallest isoform of human tau (6, 7). Furthermore, administration of the MT-stabilizing agents paclitaxel and epothilone D to human tau-expressing mice results in improved MT density and axonal integrity (8), as well as enhanced cognitive performance (9, 10). However, paclitaxel has poor blood-brain barrier (BBB) permeability and thus is unsuitable for clinical treatment of brain diseases. Epothilone D is BBB-permeable; however, as a general MT stabilizer and genotoxic agent, it may have side effects such as neuropathy and neutropenia.In this study, we aimed to find new strategies for mitigating tau toxicity by identifying...

Sucrose, one of the main products of photosynthesis in plants, functions as a universal biomarker for nutritional content and maturity of different fruits across diverse ecological niches. Drosophila melanogaster congregates to lay eggs in rotting fruits, yet the factors that influence these decisions remains uncovered. Here, we report that lactic acid bacteria Enterococci are critical modulators to attract Drosophila to lay eggs on decaying food. Drosophila-associated Enterococci predominantly catabolize sucrose for growing their population in fly food, and thus generate a unique ecological niche with depleted sucrose, but enriched bacteria. Female flies navigate these favorable oviposition sites by probing the sucrose cue with their gustatory sensory neurons. Acquirement of indigenous microbiota facilitated the development and systemic growth of Drosophila, thereby benefiting the survival and fitness of their offspring. Thus, our finding highlights the pivotal roles of commensal bacteria in influencing host behavior, opening the door to a better understanding of the ecological relationships between the microbial and metazoan worlds.

Hypoparathyroidism, mental retardation and facial dysmorphism (HRD) is a fatal developmental disease caused by mutations in tubulin-specific chaperone E (TBCE). A mouse Tbce mutation causes progressive motor neuronopathy. To dissect the functions of TBCE and the pathogenesis of HRD, we generated mutations in Drosophila tbce, and manipulated its expression in a tissue-specific manner. Drosophila tbce nulls are embryonic lethal. Tissue-specific knockdown and overexpression of tbce in neuromusculature resulted in disrupted and increased microtubules, respectively. Alterations in TBCE expression also affected neuromuscular synapses. Genetic analyses revealed an antagonistic interaction between TBCE and the microtubule-severing protein Spastin. Moreover, treatment of muscles with the microtubule-depolymerizing drug nocodazole implicated TBCE as a tubulin polymerizing protein.Taken together, our results demonstrate that TBCE is required for the normal development and function of neuromuscular synapses and that it promotes microtubule formation. As defective microtubules are implicated in many neurological and developmental diseases, our work on TBCE may offer novel insights into their basis.