Differential effect of HDAC3 on cytoplasmic and nuclear huntingtin aggregates.

Tatsuo Mano,Shoji Tsuji,Atsushi Iwata,Takayoshi Suzuki,Yoshitaka Nagai

doi:10.1371/journal.pone.0111277

Tatsuo Mano, Shoji Tsuji + Show 3 more

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https://doi.org/10.1371/journal.pone.0111277

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Abstract

Histone deacetylases (HDACs) are potential therapeutic targets of polyglutamine (pQ) diseases including Huntington’s disease (HD) that may function to correct aberrant transcriptional deactivation caused by mutant pQ proteins. HDAC3 is a unique class 1 HDAC found in both the cytoplasm and in the nucleus. However, the precise functions of HDAC3 in the two cellular compartments are only vaguely known. HDAC3 directly binds to huntingtin (Htt) with short pQ and this interaction is important for suppressing neurotoxicity induced by HDAC3. With long pQ Htt, the interaction with HDAC3 is inhibited, and this supposedly promotes neuronal death, indicating that HDAC3 would be a good therapeutic target for HD. However, the knockout of one HDAC3 allele did not show any efficacy in reducing neurodegenerative symptoms in a mouse model of HD. Therefore, the role of HDAC3 in the pathogenesis of HD has yet to be fully elucidated. We attempted to resolve this issue by focusing on the different roles of HDAC3 on cytoplasmic and nuclear Htt aggregates. In addition to supporting the previous findings, we found that HDAC3 preferentially binds to nuclear Htt over cytoplasmic ones. Specific HDAC3 inhibitors increased the total amount of Htt aggregates by increasing the amount of nuclear aggregates. Both cytoplasmic and nuclear Htt aggregates were able to suppress endogenous HDAC3 activity, which led to decreased nuclear proteasome activity. Therefore, we concluded that Htt aggregates impair nuclear proteasome activity through the inhibition of HDAC3. Our findings provide new insights regarding cross-compartment proteasome regulation.

Highlights

In polyglutamine diseases, the gene transcription machinery required for proper neuronal function is impaired, and this may result from the sequestration of essential proteins for transcription [1,2,3,4] and/or the abnormal hypo-acetylation of the genome [5]
None of the HDAC3 inhibitors showed a significant effect on Htt exon-1 (Htt-ex1) mRNA levels (Fig. 1G, H); we concluded that HDAC3 inhibition affected the intracellular Htt-ex1 aggregate degradation pathway
The key amino acids for HDAC3 activity were predicted to be the 166th and 168th aspartates; we mutated these amino acids to alanine, which successfully resulted in the loss of deacetylase activity (Fig. 2A)

Summary

Introduction

In polyglutamine (pQ) diseases, the gene transcription machinery required for proper neuronal function is impaired, and this may result from the sequestration of essential proteins for transcription [1,2,3,4] and/or the abnormal hypo-acetylation of the genome [5]. The up-regulation of transcription by histone deacetylase (HDAC) inhibitors was shown to be an effective treatment in a fly model of pQ disease [6]. Multiple studies have shown that HDAC inhibitors ameliorate symptoms and pathology in various models of Huntington’s disease (HD), one of the major pQ diseases [7,8,9,10,11]. Considering that the inhibition of HDAC6 has a negative effect on pQ degradation [12], caution is needed when interpreting data from these broad-spectrum inhibitor studies. These broad-spectrum inhibitors are not suitable for use as actual medicines to be administered to human subjects because of the potential for unwanted side effects

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