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Purification of H3 and H4 Histone Proteins and the Quantification of Acetylated Histone Marks in Cells and Brain Tissue
Published on: November 30, 2018
Intracellular trafficking of histone deacetylase 4 regulates neuronal cell death
Timothy A Bolger1, Tso-Pang Yao
1Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710, USA.
Abstract:
Histone deacetylase 4 (HDAC4) undergoes signal-dependent shuttling between the cytoplasm and nucleus, which is regulated in part by calcium/calmodulin-dependent kinase (CaMK)-mediated phosphorylation. Here, we report that HDAC4 intracellular trafficking is important in regulating neuronal cell death. HDAC4 is normally localized to the cytoplasm in brain tissue and cultured cerebellar granule neurons (CGNs). However, in response to low-potassium or excitotoxic glutamate conditions that induce neuronal cell death, HDAC4 rapidly translocates into the nucleus of cultured CGNs. Treatment with the neuronal survival factor BDNF suppresses HDAC4 nuclear translocation, whereas a proapoptotic CaMK inhibitor stimulates HDAC4 nuclear accumulation. Moreover, ectopic expression of nuclear-localized HDAC4 promotes neuronal apoptosis and represses the transcriptional activities of myocyte enhancer factor 2 and cAMP response element-binding protein, survival factors in neurons. In contrast, inactivation of HDAC4 by small interfering RNA or HDAC inhibitors suppresses neuronal cell death. Finally, an increase of nuclear HDAC4 in granule neurons is also observed in weaver mice, which harbor a mutation that promotes CGN apoptosis. Our data identify HDAC4 and its intracellular trafficking as key effectors of multiple pathways that regulate neuronal cell death.
Insights
Histone deacetylase 4 (HDAC4) nuclear translocation promotes neuronal cell death. Inhibiting HDAC4 or its nuclear import protects neurons, identifying HDAC4 trafficking as a key regulator of neuronal apoptosis.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Histone deacetylase 4 (HDAC4) regulates gene expression through deacetylation.
- HDAC4 shuttles between cytoplasm and nucleus, influenced by calcium/calmodulin-dependent kinase (CaMK).
- Neuronal cell death pathways are complex and involve protein localization dynamics.
Purpose of the Study:
- To investigate the role of HDAC4 intracellular trafficking in neuronal cell death.
- To determine the impact of HDAC4 nuclear translocation on neuronal survival and apoptosis.
- To explore HDAC4's involvement in known neuronal survival pathways.
Main Methods:
- Studied HDAC4 localization in cultured cerebellar granule neurons (CGNs) under various stress conditions.
- Utilized BDNF treatment and CaMK inhibitors to modulate HDAC4 trafficking.
- Employed ectopic expression of nuclear-localized HDAC4 and small interfering RNA (siRNA) for HDAC4 inactivation.
- Examined transcriptional activity of MEF2 and CREB.
- Analyzed HDAC4 levels in weaver mice models.
Main Results:
- HDAC4 normally resides in the cytoplasm of CGNs but translocates to the nucleus during low-potassium or excitotoxic glutamate-induced cell death.
- Brain-derived neurotrophic factor (BDNF) inhibits HDAC4 nuclear translocation, while a CaMK inhibitor promotes it.
- Nuclear HDAC4 expression enhances neuronal apoptosis and represses transcription factors MEF2 and CREB.
- HDAC4 inactivation via siRNA or HDAC inhibitors reduces neuronal cell death.
- Increased nuclear HDAC4 is observed in CGNs of weaver mice.
Conclusions:
- HDAC4 intracellular trafficking is critical for regulating neuronal cell death.
- Nuclear translocation of HDAC4 is a pro-apoptotic event in neurons.
- HDAC4 influences neuronal survival by modulating transcription factors like MEF2 and CREB.
- Targeting HDAC4 or its trafficking offers a potential therapeutic strategy for neurodegenerative diseases.
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