Abstract
Lithium is an effective mood stabilizer that has been clinically used to treat bipolar disorder for several decades. Recent studies have suggested that lithium possesses robust neuroprotective and anti-tumor properties. Thus far, a large number of lithium targets have been discovered. Here, we report for the first time that HDAC1 is a target of lithium. Lithium significantly down-regulated HDAC1 at the translational level by targeting HDAC1 mRNA. We also showed that depletion of HDAC1 is essential for the neuroprotective effects of lithium and for the lithium-mediated degradation of mutant huntingtin through the autophagic pathway. Our studies explain the multiple functions of lithium and reveal a novel mechanism for the function of lithium in neurodegeneration.
Keywords:
Autophagy; Cell Biology; Cell Signaling; Histone Deacetylase; Histone Deacetylase Inhibitors; Huntington Disease; MicroRNA; Neurodegeneration.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Autophagy
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CELF1 Protein
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Down-Regulation / drug effects
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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HEK293 Cells
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HeLa Cells
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Histone Deacetylase 1 / antagonists & inhibitors*
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Histone Deacetylase 1 / genetics*
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Histone Deacetylase 1 / metabolism
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Histone Deacetylase Inhibitors / pharmacology
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Humans
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Huntingtin Protein
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Lithium / pharmacology*
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Mutant Proteins / genetics*
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Mutant Proteins / metabolism*
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Nerve Tissue Proteins / genetics*
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Nerve Tissue Proteins / metabolism*
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Neuroprotective Agents / pharmacology
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Proteolysis / drug effects
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA-Binding Proteins / metabolism
Substances
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CELF1 Protein
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CELF1 protein, human
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HTT protein, human
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Histone Deacetylase Inhibitors
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Huntingtin Protein
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Mutant Proteins
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Nerve Tissue Proteins
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Neuroprotective Agents
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RNA, Messenger
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RNA-Binding Proteins
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Lithium
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Glycogen Synthase Kinase 3 beta
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Glycogen Synthase Kinase 3
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HDAC1 protein, human
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Histone Deacetylase 1