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Human Molecular Genetics Advance Access originally published online on September 1, 2008
Human Molecular Genetics 2008 17(23):3767-3775; doi:10.1093/hmg/ddn273
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Inhibition of specific HDACs and sirtuins suppresses pathogenesis in a Drosophila model of Huntington’s disease

Judit Pallos1, Laszlo Bodai1,{dagger}, Tamas Lukacsovich1, Judith M. Purcell1, Joan S. Steffan2, Leslie Michels Thompson2,3,4 and J. Lawrence Marsh1,5,*

1 Department of Developmental and Cell Biology 2 Department of Psychiatry and Human Behavior 3 Department of Neurobiology and Behavior 4 Department of Biological Chemistry 5 Department of Pathology, University of California, Irvine, CA 92697, USA

* To whom correspondence should be addressed at: University of California, 4444 McGaugh Hall, Irvine, CA 92697, USA. Tel: +1 9498246677; Fax: +1 9498243571; Email: jlmarsh{at}uci.edu

Received July 8, 2008; Revised August 21, 2008; Accepted August 27, 2008

Huntington’s disease (HD) is associated with transcriptional dysregulation, and multiple studies with histone deacetylase (HDAC) inhibitors suggest that global approaches for restoring transcriptional balance and appropriate protein acetylation are therapeutically promising. To determine whether more targeted approaches might be effective, we have tested the impact of all the HDACs in Drosophila on Huntingtin (Htt)-induced pathology. Among the zinc-dependent or ‘classic’ HDACs, we find that neurodegeneration is most sensitive to levels of Rpd3. We also find that among the NAD+-dependent class III deacetylases, genetic or pharmacological reduction of either Sir2 or Sirt2 provides neuroprotection to Htt-challenged animals and that even greater neuroprotection is achieved when Rpd3 and Sir2 are simultaneously reduced. Our experiments suggest that longevity promoting strategies may be distinct from those that protect against neurodegeneration in Drosophila challenged with mutant human Htt. These results highlight a novel therapeutic approach for HD in the form of Sir2 inhibition and possible combinatorial inhibition of Sir2 and Rpd3.

{dagger} Present address: Department of Biochemistry and Molecular Biology, University of Szeged, Középfasor 52, H-6726 Szeged, Hungary.


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