Proceedings of the National Academy of Sciences of the United States of America · 2010
SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Luthi-Carter Ruth, Taylor David M, Pallos Judit, Lambert Emmanuel, Amore Allison, Parker Alex, Moffitt Hilary, Smith Donna L, Runne Heike, Gokce Ozgun, Kuhn Alexandre, Xiang Zhongmin, Maxwell Michele M, Reeves Steven A, Bates Gillian P, Neri Christian, Thompson Leslie M, Marsh J Lawrence, Kazantsev Aleksey G
Аннотация
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.