Gan L, Mucke L. Paths of convergence: Sirtuins in aging and neurodegeneration. Neuron. 58: 10-14

Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA.
Neuron (Impact Factor: 15.05). 05/2008; 58(1):10-4. DOI: 10.1016/j.neuron.2008.03.015
Source: PubMed


Members of the sirtuin family of protein deacetylases support and promote longevity in diverse organisms and can extend life span when upregulated. Sirtuin pathways also modulate fundamental mechanisms in aging-related neurodegenerative diseases, including protein aggregation, stress responses, mitochondrial homeostasis, and inflammatory processes. In this minireview, we will discuss how progress in understanding the neurobiology of sirtuins is shedding light on the pathogenesis of these devastating conditions. We will also examine the potential and challenges of targeting sirtuin pathways therapeutically.

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Available from: Li Gan, Sep 29, 2014
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    • "Sirtuins are conserved family of proteins that depend on nicotinamide adenine dinucleotide (NAD + ) for their deacetylase activity (North and Verdin, 2004; Sauve and Youn, 2012). They are involved in various biological functions (Finkel et al., 2009) such as control of aging (Tissenbaum and Guarente, 2001; Wood et al., 2004), longevity pathways (Gan and Mucke, 2008), DNA repair (Lombard et al., 2008), transcriptional silencing (Tissenbaum and Guarente, 2001), apoptosis (Cohen et al., 2004; Wang et al., 2006) and the control of metabolic enzymes (Schwer and Verdin, 2008). Apart from all these functions sirtuins mainly function as anti-aging genes and their NAD + dependence categorize them as a link between aging and metabolism (Guarente, 2007). "
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    ABSTRACT: The energy production and metabolic homeostasis are well-orchestrated networks of carbohydrate, lipid and protein metabolism. These metabolic pathways are integrated by a key cytoplasmic organelle, the mitochondria, leading to production of many metabolic intermediates and harvest cellular energy in the form of ATP. Sirtuins are a highly conserved family of proteins that mediate cellular physiology and energy demands in response to metabolic inputs. Mitochondria inhabit three main types of sirtuins classified as Sirt3, Sirt4 and Sirt5. These sirtuins regulate mitochondrial metabolic functions mainly through controlling post-translational modifications of mitochondrial protein. However, the biological mechanism involved in controlling mitochondrial metabolic functions is not well understood at this stage. In this review the current knowledge on how mitochondrial sirtuins govern mitochondrial functions including energy production, metabolism, biogenesis and their involvement in different metabolic pathways are discussed. The identifications of potential pharmacological targets of sirtuins in the mitochondria and the bioactive compounds that target mitochondrial sirtuins will increase our understanding on regulation of mitochondrial metabolism in normal and disease state.
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    • "The requirement of NAD + for deacetylation makes SIRT1 an ideal mediator of the cross-talk between metabolism and epigenetic regulation. Deacetylation of histones and non-histone substrates by SIRT1 regulates metabolism, genome stability, cell survival and inflammation (Feige and Auwerx, 2008; Gan and Mucke, 2008; Oberdoerffer et al., 2008; Vaziri et al., 2001). Previous studies have implicated SIRT1 in the neuron/astrocyte fate choice during differentiation of embryonic and adult NSCs (Hisahara et al., 2008; Prozorovski et al., 2008; Saharan et al., 2013). "
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    ABSTRACT: The balance between self-renewal and differentiation of adult neural stem cells (aNSCs) is essential for the maintenance of the aNSC reservoir and the continuous supply of new neurons, but how this balance is fine-tuned in the adult brain is not fully understood. Here, we investigate the role of SIRT1, an important metabolic sensor and epigenetic repressor, in regulating adult hippocampal neurogenesis in mice. We found that there was an increase in SIRT1 expression during aNSC differentiation. In Sirt1 knockout (KO) mice, as well as in brain-specific and inducible stem cell-specific conditional KO mice, the proliferation and self-renewal rates of aNSCs in vivo were elevated. Proliferation and self-renewal rates of aNSCs and adult neural progenitor cells (aNPCs) were also elevated in neurospheres derived from Sirt1 KO mice and were suppressed by the SIRT1 agonist resveratrol in neurospheres from wild-type mice. In cultured neurospheres, 2-deoxy-D-glucose-induced metabolic stress suppressed aNSC/aNPC proliferation, and this effect was mediated in part by elevating SIRT1 activity. Microarray and biochemical analysis of neurospheres suggested an inhibitory effect of SIRT1 on Notch signaling in aNSCs/aNPCs. Inhibition of Notch signaling by a γ-secretase inhibitor also largely abolished the increased aNSC/aNPC proliferation caused by Sirt1 deletion. Together, these findings indicate that SIRT1 is an important regulator of aNSC/aNPC self-renewal and a potential mediator of the effect of metabolic changes.
    Development 12/2014; 141(24):4697-4709. DOI:10.1242/dev.117937 · 6.46 Impact Factor
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    • "HDAC6 rescues neurodegeneration and closely links between autophagy and the UPS [11]. SIRT2 is also well studied in the relationship with both brain physiology (physiological brain aging) and aging-related neurodegenerative diseases (Alzheimer disease, poly glutamine (polyQ) disease, Parkinson disease) [12,13]. These findings clearly indicate that acetylation regulates, at least in part, protein clearance to maintain cellular homeostasis during the brain ageing. "
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    ABSTRACT: Mdm20 is an auxiliary subunit of the NatB complex, which includes Nat5, the catalytic subunit for protein N-terminal acetylation. The NatB complex catalyzes N-acetylation during de novo protein synthesis initiation; however, recent evidence from yeast suggests that NatB also affects post-translational modification of tropomyosin, which is involved in intracellular sorting of aggregated proteins. We hypothesized that an acetylation complex such as NatB may contribute to protein clearance and/or proteostasis in mammalian cells. Using a poly glutamine (polyQ) aggregation system, we examined whether the NatB complex or its components affect protein aggregation in rat primary cultured hippocampal neurons and HEK293 cells. The number of polyQ aggregates increased in Mdm20 over-expressing (OE) cells, but not in Nat5-OE cells. Conversely, in Mdm20 knockdown (KD) cells, but not in Nat5-KD cells, polyQ aggregation was significantly reduced. Although Mdm20 directly associates with Nat5, the overall cellular localization of the two proteins was slightly distinct, and Mdm20 apparently co-localized with the polyQ aggregates. Furthermore, in Mdm20-KD cells, a punctate appearance of LC3 was evident, suggesting the induction of autophagy. Consistent with this notion, phosphorylation of Akt, most notably at Ser473, was greatly reduced in Mdm20-KD cells. These results demonstrate that Mdm20, the so-called auxiliary subunit of the translation-coupled protein N-acetylation complex, contributes to protein clearance and/or aggregate formation by affecting the phosphorylation level of Akt indepenently from the function of Nat5.
    PLoS ONE 12/2013; 8(12):e82523. DOI:10.1371/journal.pone.0082523 · 3.23 Impact Factor
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