Neuroprotective Effects of Phenylbutyrate in the N171-82Q Transgenic Mouse Model of Huntington's Disease

Gabriella Gardian,Susan E Browne,Dong-Kug Choi,Peter Klivenyi,Jason Gregorio,James K Kubilus,Hoon Ryu,Brett Langley,Rajiv R Ratan,Robert J Ferrante,M Flint Beal

doi:10.1074/jbc.m410210200

Abstract

Huntington's disease (HD) is caused by an expansion of exonic CAG triplet repeats in the gene encoding the huntingtin protein (Htt), however, the means by which neurodegeneration occurs remains obscure. There is evidence that mutant Htt interacts with transcription factors leading to reduced histone acetylation. We report that administration of the histone deacetylase inhibitor phenylbutyrate after onset of symptoms in a transgenic mouse model of HD significantly extends survival and attenuates both gross brain and neuronal atrophy. Administration of phenylbutyrate increased brain histone acetylation and decreased histone methylation levels as assessed by both immunocytochemistry and Western blots. Phenylbutyrate increased mRNA for components of the ubiquitin-proteosomal pathway and down-regulated caspases implicated in apoptotic cell death, and active caspase 3 immunoreactivity in the striatum. These results show that administration of phenylbutyrate, at doses that are well tolerated in man, exerts significant neuroprotective effects in a transgenic mouse model of HD, and therefore represents a very promising therapeutic approach for HD.

Highlights

Huntington’s disease (HD) is caused by an expansion of exonic CAG triplet repeats in the gene encoding the huntingtin protein (Htt), the means by which neurodegeneration occurs remains obscure
Histone acetylation is reduced in cell lines that express a mutant androgen receptor with an expanded polyglutamine repeat, and this is reversed by overexpression of CREB-binding protein (CBP) or by treatment with histone deacetylase (HDAC) inhibitors, with a concomitant reduction in cell loss [11]
We found that the HDAC inhibitor phenylbutyrate exerts significant effects on survival and ameliorates histopathologic degeneration in the N171-82Q transgenic mouse model of HD when administered after the onset of symptoms

Summary

Introduction

Huntington’s disease (HD) is caused by an expansion of exonic CAG triplet repeats in the gene encoding the huntingtin protein (Htt), the means by which neurodegeneration occurs remains obscure. Phenylbutyrate increased mRNA for components of the ubiquitin-proteosomal pathway and down-regulated caspases implicated in apoptotic cell death, and active caspase 3 immunoreactivity in the striatum These results show that administration of phenylbutyrate, at doses that are well tolerated in man, exerts significant neuroprotective effects in a transgenic mouse model of HD, and represents a very promising therapeutic approach for HD. Histone acetylation is reduced in cell lines that express a mutant androgen receptor with an expanded polyglutamine repeat, and this is reversed by overexpression of CBP or by treatment with HDAC inhibitors, with a concomitant reduction in cell loss [11]. We found that the HDAC inhibitor phenylbutyrate exerts significant effects on survival and ameliorates histopathologic degeneration in the N171-82Q transgenic mouse model of HD when administered after the onset of symptoms. We show for the first time that histone methylation is markedly increased in the N171-82Q transgenic mouse model of HD, and that this is ameliorated by phenylbutyrate treatment

Methods

Results

Conclusion