SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis

Ruth Luthi-Carter; 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

doi:10.1073/pnas.1002924107

SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis

Ruth Luthi-Carter, 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

Medical & Molecular Genetics

Research output: Contribution to journal › Article › peer-review

285 Citations (Scopus)

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.

Original language	English
Pages (from-to)	7927 - 7932
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	107
Issue number	17
DOIs	https://doi.org/10.1073/pnas.1002924107
Publication status	Published - 27 Apr 2010

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Luthi-Carter, R., Taylor, D. M., Pallos, J., Lambert, E., Amore, A., Parker, A., Moffitt, H., Smith, D. L., Runne, H., Gokce, O., Kuhn, A., Xiang, Z., Maxwell, M. M., Reeves, S. A., Bates, G. P., Neri, C., Thompson, L. M., Marsh, J. L., & Kazantsev, A. G. (2010). SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis. Proceedings of the National Academy of Sciences of the United States of America, 107(17), 7927 - 7932. https://doi.org/10.1073/pnas.1002924107

@article{a0a9a1f70a474bd5a24e745d9cbf67bd,

title = "SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis",

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.",

author = "Ruth Luthi-Carter and Taylor, {David M.} and Judit Pallos and Emmanuel Lambert and Allison Amore and Alex Parker and Hilary Moffitt and Smith, {Donna L.} and Heike Runne and Ozgun Gokce and Alexandre Kuhn and Zhongmin Xiang and Maxwell, {Michele M.} and Reeves, {Steven A.} and Bates, {Gillian P.} and Christian Neri and Thompson, {Leslie M.} and Marsh, {J. Lawrence} and Kazantsev, {Aleksey G.}",

year = "2010",

month = apr,

day = "27",

doi = "10.1073/pnas.1002924107",

language = "English",

volume = "107",

pages = "7927 -- 7932",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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publisher = "National Acad Sciences",

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Luthi-Carter, R, Taylor, DM, Pallos, J, Lambert, E, Amore, A, Parker, A, Moffitt, H, Smith, DL, Runne, H, Gokce, O, Kuhn, A, Xiang, Z, Maxwell, MM, Reeves, SA, Bates, GP, Neri, C, Thompson, LM, Marsh, JL & Kazantsev, AG 2010, 'SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 17, pp. 7927 - 7932. https://doi.org/10.1073/pnas.1002924107

TY - JOUR

T1 - SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis

AU - Luthi-Carter, Ruth

AU - Taylor, David M.

AU - Pallos, Judit

AU - Lambert, Emmanuel

AU - Amore, Allison

AU - Parker, Alex

AU - Moffitt, Hilary

AU - Smith, Donna L.

AU - Runne, Heike

AU - Gokce, Ozgun

AU - Kuhn, Alexandre

AU - Xiang, Zhongmin

AU - Maxwell, Michele M.

AU - Reeves, Steven A.

AU - Bates, Gillian P.

AU - Neri, Christian

AU - Thompson, Leslie M.

AU - Marsh, J. Lawrence

AU - Kazantsev, Aleksey G.

PY - 2010/4/27

Y1 - 2010/4/27

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.1002924107

DO - 10.1073/pnas.1002924107

M3 - Article

SN - 1091-6490

VL - 107

SP - 7927

EP - 7932

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 17

ER -

SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis

Abstract

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