Comparison of Sirtuin 3 Levels in ALS and Huntington's Disease-Differential Effects in Human Tissue Samples vs. Transgenic Mouse Models.

Eva Buck,Anke Witting,Katrin S Lindenberg,Hanna Bayer,Albert C Ludolph,Patrick Weydt,Noemi Pasquarelli,Johannes Hanselmann

doi:10.3389/fnmol.2017.00156

Eva Buck, Anke Witting + Show 6 more

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https://doi.org/10.3389/fnmol.2017.00156

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Abstract

Neurodegenerative diseases are characterized by distinct patterns of neuronal loss. In amyotrophic lateral sclerosis (ALS) upper and lower motoneurons degenerate whereas in Huntington’s disease (HD) medium spiny neurons in the striatum are preferentially affected. Despite these differences the pathophysiological mechanisms and risk factors are remarkably similar. In addition, non-neuronal features, such as weight loss implicate a dysregulation in energy metabolism. Mammalian sirtuins, especially the mitochondrial NAD+ dependent sirtuin 3 (SIRT3), regulate mitochondrial function and aging processes. SIRT3 expression depends on the activity of the metabolic master regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a modifier of ALS and HD in patients and model organisms. This prompted us to systematically probe Sirt3 mRNA and protein levels in mouse models of ALS and HD and to correlate these with patient tissue levels. We found a selective reduction of Sirt3 mRNA levels and function in the cervical spinal cord of end-stage ALS mice (superoxide dismutase 1, SOD1G93A). In sharp contrast, a tendency to increased Sirt3 mRNA levels was found in the striatum in HD mice (R6/2). Cultured primary neurons express the highest levels of Sirt3 mRNA. In primary cells from PGC-1α knock-out (KO) mice the Sirt3 mRNA levels were highest in astrocytes. In human post mortem tissue increased mRNA and protein levels of Sirt3 were found in the spinal cord in ALS, while Sirt3 levels were unchanged in the human HD striatum. Based on these findings we conclude that SIRT3 mediates the different effects of PGC-1α during the course of transgenic (tg) ALS and HD and in the human conditions only partial aspects Sirt3 dysregulation manifest.

Highlights

Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD) show distinct patterns of progressive neuronal cell loss
First we measured sirtuin 3 (Sirt3) mRNA and protein levels, in informative brain regions of wt mice. These were high in the brain stem and spinal cord, two regions prominently affected in ALS (Figures 1A,D, FIGURE 1 | Distribution of mitochondrial sirtuins in different regions of the murine central nervous system (CNS)
Sirtuin 4 (Sirt4) mRNA levels were expressed across the different brain regions (Figure 1B), while sirtuin 5 (Sirt5) mRNA expression showed a region specific distribution similar to Sirt3 (Figure 1C)

Summary

Introduction

Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD) show distinct patterns of progressive neuronal cell loss. ALS and HD patients show hypermetabolic features (Dupuis et al, 2004, 2011; Aziz et al, 2010; Tefera and Borges, 2017). These include loss of body weight, in spite of increased food intake (Djousse et al, 2002; Dupuis et al, 2011), and suggest an increase in energy expenditure (Dupuis et al, 2004, 2011; Aziz et al, 2008). The mitochondrial changes in ALS and HD are reminiscent of mitochondrial alterations during aging including the decreased capacity to cope with oxidative stress (Mecocci et al, 1993) and an increased rate of mitochondrial DNA (mtDNA) mutations (Lin and Beal, 2006)

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