The role of calorie restriction and SIRT1 in prion-mediated neurodegeneration
Introduction
Aging research has the potential to impact a broad array of aging-related diseases (Sinclair and Guarente, 2006, Chen and Guarente, 2007). Calorie restriction (CR) is a dietary regimen that extends lifespan in a wide spectrum of species ranging from yeast to mammals (Guarente and Picard, 2005). CR also delays many diseases with seemingly different causes, such as kidney disease, cancer, autoimmune disease, metabolic syndromes, and neurodegenerative diseases including Parkinson’s and Alzheimer’s disease (Koubova and Guarente, 2003, Chen et al., 2005b, Longo and Kennedy, 2006). Mediators of CR would serve as potential targets for a CR mimetic (Baur and Sinclair, 2006).
The Sir2 gene was first identified as a longevity factor in yeast, and this function is conserved in higher organisms (Guarente and Picard, 2005). The Sir2 protein is an NAD-dependent deacetylase (Imai et al., 2000). Thus, its activity is amenable for regulation by the metabolic status of the cell, and it may serve as a prime candidate in mediating the cellular responses to CR. There is evidence that Sir2 is required for CR-induced lifespan extension in yeast and flies, although in yeast the requirement of Sir2 might depend on the specific conditions of CR (Longo and Kennedy, 2006, Chen and Guarente, 2007). SIRT1, the mammalian ortholog of the yeast Sir2, is required for the increased physical activity exhibited in CR mice (Chen et al., 2005a). In addition, transgenic mice overexpressing SIRT1 in certain tissues show some metabolic phenotypes resembling those seen in mice on a CR regimen (Bordone et al., 2007). Thus, it is relevant and critical to address whether SIRT1 mediates both CR-induced lifespan extension and the delay of aging-related diseases in mammals.
The expression of SIRT1 promotes longevity by an as yet undetermined mechanism that may involve its upregulation in many tissues of mice on a CR diet (Cohen et al., 2004). It is also thought to have a protective role in the progression of many neurodegenerative diseases. SIRT1 may serve as a downstream effector of increased NAD biosynthesis and delay axonal degeneration in a mouse model of Wallerian degeneration (Araki et al., 2004). Importantly, overexpression of SIRT1 also protects against Alzheimer’s disease, Huntington’s disease and amyotrophic lateral sclerosis in various model systems (Parker et al., 2005, Qin et al., 2006, Kim et al., 2007), consistent with its proposed neuroprotective function. However, the effect of deleting SIRT1 in a neurodegenerative disease model in a mammalian system is not known.
Prion diseases are unique among neurodegenerative diseases in that they are transmissible while still sharing commonalities with other neurodegenerative diseases such as the accumulation of aggregates of misfolded protein, a prominent astrocytic and microglial response, and loss of neurons in the central nervous system (Prusiner, 1998, Aguzzi et al., 2007). The prion protein (PrP) is an N-linked glycoprotein tethered to the cell surface via a GPI anchor. Although the normal function of PrP is poorly defined (Steele et al., 2007a), numerous lines of evidence point toward a pivotal role for PrP in the pathogenic mechanism of prion diseases (Prusiner, 1998, Aguzzi et al., 2007). In prion diseases, the normal isoform of PrP (termed PrPC) is structurally converted into PrPSc, a self-perpetuating and aggregation-prone conformation of the protein (Prusiner, 1998). The ongoing conversion of PrPC to PrPSc in neurons is required for prion toxicity (Brandner et al., 1996, Mallucci et al., 2003, Aguzzi and Heikenwalder, 2006). Yet beyond this basic observation, the pathways leading to neurotoxicity are almost completely unknown (Aguzzi et al., 2007, Steele et al., 2007b).
Here we investigate the effects of CR and SIRT1 deletion in a mouse model of infectious prion disease. In contrast to both what has been observed with Sir2 deletion in a worm model of polyglutamine disease (Parker et al., 2005) and what would be predicted based on studies where SIRT1 is overexpressed in mouse models of neurodegeneration (Qin et al., 2006, Kim et al., 2007), SIRT1 deletion delays the onset of disease. As expected, CR delays the onset of disease, consistent with what has been observed with other models of neurodegeneration (Duan et al., 2003, Patel et al., 2005). Both CR and SIRT1 deletion delay the onset of prion disease by mechanisms that may involve a reduction in PrP expression, a well characterized determinant of the onset and duration of prion disease (Weissmann et al., 1998). Unexpectedly, CR also greatly shortens the duration of the clinical period of the disease in a manner that is independent of SIRT1. Despite the delay in disease onset, mice on a CR diet ultimately succumb to disease slightly faster than controls on a normal diet, in contrast to what has been observed with CR and other neurodegenerative disease models (Duan et al., 2003, Patel et al., 2005). Regulation of SIRT1 expression by CR differs in various brain regions; expression of SIRT1 was upregulated by CR in the cortex and hippocampus, and downregulated in the cerebellum and midbrain. Thus, SIRT1 regulation in the brain during CR is complex, a finding which is consistent with the unexpected effects of CR and SIRT1 deletion on prion-mediated neurodegeneration.
Section snippets
The onset of prion disease is delayed by CR and in SIRT1 knockout mice
To assess the effects of CR and SIRT1 on prion disease, we compared the response to prion infection of SIRT1 knockout mice (KO) (McBurney et al., 2003) and their wild type (WT) littermates either fed ad libitum (AL) or on a CR diet. One month after mice were adjusted to CR, we challenged them (WT/AL, WT/CR, SIRT1 KO/AL, and SIRT1 KO/CR) with 3.5 log LD50 Rocky Mountain Laboratory (RML) strain of murine prions inoculated directly into the brain.
Prior to the onset of overt symptoms we sacrificed a
Discussion
We propose the following mechanism for the relationship between CR, SIRT1 and prion disease: SIRT1 is downregulated in certain brain regions of CR mice, resulting in a decreased PrP expression level, PrPSc accumulation, and delayed onset of prion disease. The following evidence supports such a model: (1) Both SIRT1 deletion and CR delay the onset of prion disease, and CR has no further effect on SIRT1 KO mice (Fig. 1, Fig. 2). This suggests that the effects of SIRT1 deletion and CR on the onset
Mouse strains, calorie restriction, and prion inoculations
All animal procedures were in accordance with the conditions set forth by the MIT animal care committee. SIRT1 KOs have been described previously (McBurney et al., 2003); these mice are maintained on an outbred genetic background consisting of CD1 and 129/Sv. Three to four months old animals were either fed AL or subjected to a 30% CR diet, which was provided daily. Only wild type and SIRT1 KO littermates were used. For analysis of SIRT1 expression in the brain, C57Bl/6 mice on a CR diet and AL
Acknowledgments
We are grateful to Artur Topolszki and Walker Jackson (WIBR) for assistance with prion inoculations and to Vilma Martins (Ludwig Institute for Cancer Research) for providing the luciferase reporter construct. S.L. is an investigator in the Howard Hughes Medical Institute, D.C. was supported by a Leukemia and Lymphoma Society postdoctoral fellowship (5168-06) and L.G. is funded by the NIH.
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These authors contributed equally to this work.