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. 2010 Apr 27;107(17):7927-32.
doi: 10.1073/pnas.1002924107. Epub 2010 Apr 8.

SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis

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

SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis

Ruth Luthi-Carter et al. Proc Natl Acad Sci U S A. .

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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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Neuroprotective effects of SIRT2 inhibitors in invertebrate models of HD. (A) AGK2 and AK-1 decrease the degeneration of light-sensing rhabdomeres in the Drosophila eye. *, P < 0.02 (for 10 μM AGK2 or AK-1, respectively). (B and C) Heterozygous and homozygous deletion of Sirt2 shows a dose-dependent reduction in the Drosophila model of HD. AK-1 (D) and AGK2 (E) rescued the defective touch response in C. elegans expressing polyQ N-ter Htt fused to CFP in touch receptor neurons. (*, P < 0.05).
Fig. 2.
Fig. 2.
SIRT2 inhibition protects against Htt171-82Q toxicity in primary striatal neurons. (A) As shown previously, Htt171-82Q (black bar) exhibits toxicity toward striatal neurons as compared with Htt171-18Q (white bar). AK-1 rescued Htt171-82Q-expressing cells in a dose-dependent manner (at concentrations of 1, 2, and 4 μM) (A) and significantly reduced the number of mutant Htt positive inclusions (B). AGK2 also rescued striatal neurons from Htt171-82Q toxicity (C) and significantly reduced the number of inclusions (D). Overexpression of SIRT2WT abrogates neuroprotection by AK-1 (E). A lentiviral vector encoding CFP is used as a coinfection control. A dominant negative deacetylase mutant SIRT2H150Y significantly decreases Htt171-82Q toxicity in primary striatal neurons (F) and also significantly reduced the number of inclusions (G). A lentiviral vector encoding CFP is used as a coinfection control (* P < 0.05).
Fig. 3.
Fig. 3.
Gene expression and metabolic effects of SIRT2 inhibition in neurons. (A) Multiple genes controlling sterol biosynthesis are down-regulated by AK-1 treatment. Scheme depicts enzymes in sterol biosynthesis whose RNAs are down-regulated by AK-1 treatment by the criterion of FDR P < 0.05. (The segment of the pathway between acetoacetate and cholesterol is shown.) Full analyses of the data, including statistical measures, fold-changes, and Gene Ontology analyses, are presented in Dataset S1 and S2. (B–D) SIRT2 inhibition reverses Htt171-82Q-mediated increase in sterols. (B) DMSO-treated neurons expressing Htt171-82Q had significantly higher sterol levels (cholesterol and cholesteryl esters) than those expressing either CFP or Htt171-18Q and this effect was reversed by treatment with AK-1, AGK2 (5 μM, 48 hrs) (C), and SIRT2H150Y (D) (*P < 0.05).
Fig. 4.
Fig. 4.
SIRT2 inhibition reduces nuclear trafficking of SREBP-2. (A) Both AK-1 and AGK2 decrease the trafficking of endogenous SREBP-2 to the nucleus. (B) Expression of wild-type SIRT2 increases endogenous nuclear SREBP-2 whereas deacetylase-deficient SIRT2H150Y reduces this effect. (Scale bar: 10 μM.) (C) Dominant negative mutant SREBP-2NEG protects neurons against Htt171-82Q toxicity. (D) Conversely, the constitutively active mutant SREBP-2ACT enhances Htt171-82Q toxicity (*, P < 0.05).
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