Can sirtuins do no wrong? These NAD+-dependent deacetylases regulate metabolism, keep mitochondria happy, and increase longevity in animals. They might even help control Alzheimer disease (AD) by protecting neurons and by promoting non-amyloidogenic processing of amyloid-β precursor protein (see ARF related news story). That they are activated by resveratrol, a compound found in grape extracts and red wine, only adds to the caché. But in one respect sirtuins may be bad for the brain. In the March 16 Nature Cell Biology online, researchers led by Frauke Zipp and Orhan Aktas at the Charité–Universitätsmedizin Berlin, Germany, report that the sirtuin Sirt1 suppresses proliferation of neural progenitor cells and guides them toward an astroglial fate. The finding raises the possibility that in diseases where astrogliosis and neuron loss go hand-in-hand, such as AD, Sirt1 might not be the knight in shining armor that we have been led to believe.

Sirt1 deacetylates the histones that help package DNA, but the deacetylase must be led to chromatin by partners, such as transcriptional co-repressors. One of these, Hes1, prevents premature neurogenesis in the developing brain by repressing the transcription factor Mash1. Under oxidative conditions, as during inflammation, neurogenesis is also tempered in the developed brain (see ARF related news story). Since Sirt1 is activated by NAD+, which predominates during oxidative conditions (in more reduced environments NADH2 predominates), the researchers wondered if the sirtuin might somehow be involved in redox-regulated suppression of neurogenesis.

That’s exactly what joint first authors Timour Prozorovski, Ulf Schulze-Topphoff, and colleagues report. They show that the redox state of mouse cortical neural progenitor cells (NPCs) governs their fate. Cultured with redox modulators that cause an increase in reactive oxygen species, NPC proliferation suffers and their differentiation into astrocytes increases by as much as 40 percent. Neural progeny decrease by the same margin. Reducing conditions had the opposite effect. The researchers also found that Sirt1 expression increased 6.5-fold under oxidative conditions and that the Sirt1-Hes1 complex was activated, and acetylation of histone 3 at lysine 9, a target of Sirt1, was downregulated. Mash1 was also suppressed, but not if Sirt1 was silenced or inhibited.

The findings indicate that redox state acts like a switch to turn on Sirt1 and direct NPCs toward an astrocyte fate. But do redox changes have a similar effect in a more physiological environment? Indications are that they may. The researchers caused a “pro-oxidative shift” in mouse pups by administering an inhibitor of glutathione synthase—glutathione is a major source of reducing equivalents. They found that Sirt1 was increased in the subventricular zone, a major site of neurogenesis, and that there was a reduction in newly synthesized cells that stain for the neural marker doublecortin (Dcx). In contrast, knocking down Sirt1 or Hes1 in utero increased the number of Dcx-positive cells in three- to six-day-old pups, even after inhibition of glutathione synthase, indicating that Sirt1 can suppress neurogenesis in vivo.

What’s more, the researchers report that in a mouse model of multiple sclerosis (MS), Sirt1 is upregulated in areas of reactive astrogliosis while Mash1 is downregulated. Sirt1 was mainly nuclear in those areas of inflammation, indicating it may be involved in histone deacetylation. And in an experiment that might come as a disappointment to some, the researchers report that administering resveratrol to MS mice led to increased gliogenesis. Luckily, the researchers used much more resveratrol (50 mg/Kg) than can be found in your favorite bottle of Pinot noir (~2 mg/L).—Tom Fagan.

Reference:
Prozorovski T, Schulze-Topphoff U, Glumm R, Baumgart J, Schröter F, Ninnemann O, Siegert E, Bendix I, Bruüstle O, Nitsch R, Zipp F, Aktas O. Sirt1 contributes critically to the redox-dependent fate of neural progenitors. Nat Cell Biol. 2008 Mar 16; [Epub ahead of print] Abstract

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References

News Citations

  1. Aging, Acetate, and Aβ: Sirtuins Regulate Metabolism and More
  2. Antiinflammatory Drugs Protect Hippocampal Neurogenesis

Paper Citations

  1. . Sirt1 contributes critically to the redox-dependent fate of neural progenitors. Nat Cell Biol. 2008 Apr;10(4):385-94. PubMed.

Further Reading

Papers

  1. . Sirt1 contributes critically to the redox-dependent fate of neural progenitors. Nat Cell Biol. 2008 Apr;10(4):385-94. PubMed.

Primary Papers

  1. . Sirt1 contributes critically to the redox-dependent fate of neural progenitors. Nat Cell Biol. 2008 Apr;10(4):385-94. PubMed.