2. Academic Validation
  3. SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis

SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis

  • Proc Natl Acad Sci U S A. 2010 Apr 27;107(17):7927-32. doi: 10.1073/pnas.1002924107.
Ruth Luthi-Carter 1,  David M Taylor,  Judit Pallos,  Emmanuel Lambert,  Allison Amore,  Alex Parker,  Hilary Moffitt,  Donna L Smith,  Heike Runne,  Ozgun Gokce,  Alexandre Kuhn,  Zhongmin Xiang,  Michele M Maxwell,  Steven A Reeves,  Gillian P Bates,  Christian Neri,  Leslie M Thompson,  J Lawrence Marsh,  Aleksey G Kazantsev
Affiliations

Affiliation

  • 1 Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland. ruth.luthi-carter@epfl.ch
PMID: 20378838 DOI: 10.1073/pnas.1002924107
Abstract

Huntington's disease (HD), an incurable neurodegenerative disorder, has a complex pathogenesis including protein aggregation and the dysregulation of neuronal transcription and metabolism. Here, we demonstrate that inhibition of Sirtuin 2 (SIRT2) achieves neuroprotection in cellular and invertebrate models of HD. Genetic or pharmacologic inhibition of SIRT2 in a striatal neuron model of HD resulted in gene expression changes including significant down-regulation of RNAs responsible for sterol biosynthesis. Whereas mutant Huntingtin fragments increased sterols in neuronal cells, SIRT2 inhibition reduced sterol levels via decreased nuclear trafficking of SREBP-2. Importantly, manipulation of sterol biosynthesis at the transcriptional level mimicked SIRT2 inhibition, demonstrating that the metabolic effects of SIRT2 inhibition are sufficient to diminish mutant Huntingtin toxicity. These data identify SIRT2 inhibition as a promising avenue for HD therapy and elucidate a unique mechanism of SIRT2-inhibitor-mediated neuroprotection. Furthermore, the ascertainment of SIRT2's role in regulating cellular metabolism demonstrates a central function shared with other Sirtuin proteins.

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