HDAC6 mutations rescue human tau-induced microtubule defects in Drosophila.

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.

• Authors: Ying Xiong, Kai Zhao, Jiaxi Wu, Zhiheng Xu, Shan Jin, Yong Q Zhang
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 12 Pg. 4604-9 (Mar 19 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 23487739 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Drosophila Proteins
• Epothilones
• MAPT protein, human
• Mapt protein, mouse
• Tubulin Modulators
• tau Proteins
• HDAC6 protein, Drosophila
• HDAC6 protein, human
• Hdac6 protein, mouse
• Histone Deacetylase 6
• Histone Deacetylases
• Paclitaxel
• desoxyepothilone B

Topics

• Alzheimer Disease (genetics, metabolism, pathology, therapy)
• Animals
• Disease Models, Animal
• Drosophila Proteins (genetics, metabolism)
• Drosophila melanogaster
• Epothilones (pharmacology)
• Histone Deacetylase 6
• Histone Deacetylases (genetics, metabolism)
• Humans
• Mice
• Mice, Knockout
• Microtubules (genetics, metabolism, pathology)
• Muscle Cells (metabolism, pathology)
• Mutation
• Neurons (metabolism, pathology)
• Paclitaxel (pharmacology)
• Phosphorylation (drug effects, genetics)
• Tubulin Modulators (pharmacology)
• tau Proteins (genetics, metabolism)