Lithium Down-regulates Histone Deacetylase 1 (HDAC1) and Induces Degradation of Mutant Huntingtin

Abstract

Background: Lithium and valproic acid (VPA) exhibit a robust neuroprotective and anti-tumor effects in neural cells and tumor cells. Results: Lithium significantly down-regulates HDAC1 at the translational level by targeting HDAC1 mRNA. Conclusion:The decrease in HDAC1 is essential for the lithium-mediated, autophagic degradation of mutant huntingtin. Significance: This report is the first demonstration that HDAC1 decreases in response to lithium treatment.

Transmembrane domain is crucial to the subcellular localization and function of Myc target 1

“…Immunofluorescence was performed as described previously [16]. Briefly, the cells were fixed with 4% polyformaldehyde, permeabilized with 0.5% Triton X-100 and incubated in 5% BSA for 1 hr.…”

Lithium and Autophagy

“…2 In mutant huntingtin-transfected HEK 293T and HeLa cells, lithium treatment down-regulated the histone deacetylase 1 protein level and facilitated autophagic degradation of mutant huntingtin. 36 Since GSK3β inhibitors did not alter the HDAC1 level, the authors conclude that lithium-facilitated downregulation of HDAC1 is independent of GSK3β. Thus, it is likely that lithium's autophagy enhancing action related to mutated huntingtin is independent of GSK3β.…”

Understanding the molecular mechanisms underlying mood stabilizer treatments in bipolar disorder: Potential involvement of epigenetics

“…VPA promotes histone acetylation through inhibition of HDAC enzymes and increase of acetylated histone H3 and H4 levels [51]. Lithium has also been shown to be able to downregulate HDAC1 in HEK293T, SW480, and HeLa cells [54]. Lithium, VPA and carbamazepine showed a common tendency to increase global methylation levels in neuroblastoma SK-N-SH cells [56].…”

“…VPA has also been suggested to increase expression of genes that are normally repressed by causing changes in their chromatin acetylation and DNA methylation state [53]. Lithium is able to downregulate histone deacetylase 1 (HDAC1) and this effect has been shown to be essential for lithium-induced degradation of mutant huntingtin through autophagy [54]. Epigenetic alterations could also mediate some of the less desired effects induced by mood stabilizers.…”

“…Neural progenitor cells (NT2) [34] CBZ Inhibition of binding of HDAC1 to the promoter of CYP3A4 HepG2 and primary cultured hepatic cells [55] Lithium Downregulation of HDAC1 HEK293T, SW480 and HeLa cells [54] Lithium, VPA, CBZ 41 hypermethylated and 11 hypomethylated genes were commonly altered by all mood stabilizers. Lithium showed an effect on the largest number of genes.…”