SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis.
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.
Luthi-Carter
Ruth
R
Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland. ruth.luthi-carter@epfl.ch
Taylor
David M
DM
Pallos
Judit
J
Lambert
Emmanuel
E
Amore
Allison
A
Parker
Alex
A
Moffitt
Hilary
H
Smith
Donna L
DL
Runne
Heike
H
Gokce
Ozgun
O
Kuhn
Alexandre
A
Xiang
Zhongmin
Z
Maxwell
Michele M
MM
Reeves
Steven A
SA
Bates
Gillian P
GP
Neri
Christian
C
Thompson
Leslie M
LM
Marsh
J Lawrence
JL
Kazantsev
Aleksey G
AG
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D017173:Caenorhabditis elegans; D004330:Drosophila; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006816:Huntington Disease / Q000517:prevention & control*; D007150:Immunohistochemistry; D051379:Mice; D018613:Microscopy, Confocal; D018696:Neuroprotective Agents / Q000494:pharmacology*; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism*; D013261:Sterols / Q000096:biosynthesis*
D018696:Neuroprotective Agents; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D013261:Sterols; D056565:Sirtuin 2