<i>Drosophila</i> Histone Deacetylase 6 Protects Dopaminergic Neurons against α-Synuclein Toxicity by Promoting Inclusion Formation

Du, Guiping; Liu, Xiang; Chen, Xinping; Song, Mei; Yan, Yan; Jiao, Renjie; Wang, Chih-chen

doi:10.1091/mbc.e10-03-0200

Cited by 113 publications

(89 citation statements)

References 45 publications

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“…Indeed, HDAC6 inhibition would impair the removal of aggregated protein by retrograde transport to autophagosomes and lysosomes as it was shown that tubacin treatment decreased the recruitment of Atg/LC3, a crucial component of autophagic transport 51 , and that HDAC6 expression rescued neurodegeneration in a model of spinal and bulbar muscular atrophy 52 . HDAC6 has been shown also to protect dopaminergic neurons from alpha-synuclein-induced toxicity 53 . For what concerns axonal pathology, MT stability must be regulated at an optimal level to allow axon and dendrites development in neuritogenesis, and it has been demonstrated that HDAC6 is required to provide efficient MT deacetylation 54 .…”

Section: Discussionmentioning

confidence: 99%

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

et al. 2015

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Maintenance of neuronal polarity and regulation of cytoskeletal dynamics are vital during development and to uphold synaptic activity in neuronal networks. Here we show that soluble b-amyloid (Ab) disrupts actin and microtubule (MT) dynamics via activation of RhoA and inhibition of histone deacetylase 6 (HDAC6) in cultured hippocampal neurons. The contact of Ab with the extracellular membrane promotes RhoA activation, leading to growth cone collapse and neurite retraction, which might be responsible for hampered neuronal pathfinding and migration in Alzheimer's disease (AD). The inhibition of HDAC6 by Ab increases the level of heterodimeric acetylated tubulin and acetylated tau, both of which have been found altered in AD. We also find that the loss of HDAC6 activity perturbs the integrity of axon initial segment (AIS), resulting in mislocalization of ankyrin G and increased MT instability in the AIS concomitant with loss of polarized localization of tau and impairment of action potential firing.

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Section: Discussionmentioning

confidence: 99%

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

et al. 2015

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“…Most previous studies on the role of HDAC6 in neurodegenerative diseases have focused on autophagy-mediated protein degradation because aberrant accumulation of misfolded proteins is considered to be a common pathogenic mechanism in a number of these disorders. For example, overexpression of HDAC6 has been shown to be neuroprotective in Parkinson disease and Huntington disease models by promoting autophagy-mediated degradation of aggregated proteins (16,(40)(41)(42). Conversely, HDAC6 loss-of-function mutations increase Hsp90 acetylation, which promotes proteasome-mediated degradation of target proteins, including tau (43,44).…”

Section: Discussionmentioning

confidence: 99%

“…Exploitation of HDCA6 suppression for eventual tauopathy treatment has several advantages. First, both HDAC6 mutant flies and knockout mice are viable and display no obvious developmental abnormalities (16,49), greatly facilitating preclinical studies on HDCA6 function in tauopathy models. Second, there are a number of highly specific HDAC6 inhibitors available, such as tubacin and tubastatin A (26,50).…”

Section: Discussionmentioning

confidence: 99%

HDAC6 mutations rescue human tau-induced microtubule defects in Drosophila

Xiong

Zhao

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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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...

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“…The spastin-null mutant spastin 5.75 was from N. Sherwood (Sherwood et al, 2004) and a UAS-spastin line was from K. Broadie (Trotta et al, 2004). The HDAC6 null mutant (HDAC6 KO ) and the UAS-HDAC6 line were from R. Jiao (Du et al, 2010), and two UAS lines expressing mutant HDAC6 with mutation H237A or H664A in the two deacetylase domains were described previously (Xiong et al, 2013). An RNAi line of Katanin 60 (v38369) was obtained from the Vienna Drosophila RNAi Center.…”

Section: Materials and Methods Drosophila Stocks And Husbandrymentioning

confidence: 99%

Microtubule-severing protein Katanin regulates neuromuscular junction development and dendritic elaboration in Drosophila

Mao

Xiong

et al. 2014

Development

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Microtubules (MTs) are crucial for diverse biological processes including cell division, cell growth and motility, intracellular transport and the maintenance of cell shape. MT abnormalities are associated with neurodevelopmental and neurodegenerative diseases such as hereditary spastic paraplegia. Among many MT regulators, katanin was the first identified MT-severing protein, but its neuronal functions have not yet been examined in a multicellular organism. Katanin consists of two subunits; the catalytic subunit katanin 60 contains an AAA (ATPases associated with a variety of cellular activities) domain and breaks MT fibers while hydrolyzing ATP, whereas katanin 80 is a targeting and regulatory subunit. To dissect the in vivo functions of Katanin, we generated mutations in Drosophila Katanin 60 and manipulated its expression in a tissue-specific manner. Null mutants of Katanin 60 are pupal lethal, demonstrating that it is essential for viability. Loss-of-function mutants of Katanin 60 showed excess satellite boutons, reduced neurotransmission efficacy, and more enlarged cisternae at neuromuscular junctions. In peripheral sensory neurons, loss of Katanin 60 led to increased elaboration of dendrites, whereas overexpression of Katanin 60 resulted in the opposite. Genetic interaction analyses indicated that increased levels of MT acetylation increase its susceptibility to Katanin-mediated severing in neuronal and non-neuronal systems. Taken together, our results demonstrate for the first time that Katanin 60 is required for the normal development of neuromuscular synapses and dendrites.

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Drosophila Histone Deacetylase 6 Protects Dopaminergic Neurons against α-Synuclein Toxicity by Promoting Inclusion Formation

Abstract: dHDAC6 functions to suppress α-synuclein-induced neurodegeneration and locomotion defects in a Drosophila PD model through promoting α-synuclein-enriched inclusion formation while reducing the toxic oligomers.

Cited by 113 publications

References 45 publications

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

HDAC6 mutations rescue human tau-induced microtubule defects in Drosophila

Microtubule-severing protein Katanin regulates neuromuscular junction development and dendritic elaboration in Drosophila

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