SIRT2 Ablation Has No Effect on Tubulin Acetylation in Brain, Cholesterol Biosynthesis or the Progression of Huntington's Disease Phenotypes In Vivo

Hitoshi Okazawa,Anna Bobrowska,Leonard Guarente,Andreas Weiss,Gillian Bates,Gizem Donmez

doi:10.1371/journal.pone.0034805

Hitoshi Okazawa, Anna Bobrowska + Show 4 more

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https://doi.org/10.1371/journal.pone.0034805

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Abstract

Huntington's disease (HD) is a devastating neurodegenerative disorder for which there are no disease-modifying treatments. The molecular pathogenesis of HD is complex and many mechanisms and cellular processes have been proposed as potential sites of therapeutic intervention. However, prior to embarking on drug development initiatives, it is essential that therapeutic targets can be validated in mammalian models of HD. Previous studies in invertebrate and cell culture HD models have suggested that inhibition of SIRT2 could have beneficial consequences on disease progression. SIRT2 is a NAD+-dependent deacetylase that has been proposed to deacetylate α-tubulin, histone H4 K16 and to regulate cholesterol biogenesis – a pathway which is dysregulated in HD patients and HD mouse models. We have utilized mice in which SIRT2 has been reduced or ablated to further explore the function of SIRT2 and to assess whether SIRT2 loss has a beneficial impact on disease progression in the R6/2 mouse model of HD. Surprisingly we found that reduction or loss of SIRT2 had no effect on the acetylation of α-tubulin or H4K16 or on cholesterol biosynthesis in the brains of wild type mice. Equally, genetic reduction or ablation of SIRT2 had no effect on HD progression as assessed by a battery of physiological and behavioural tests. Furthermore, we observed no change in aggregate load or levels of soluble mutant huntingtin transprotein. Intriguingly, neither the constitutive genetic loss nor acute pharmacological inhibition of SIRT2 affected the expression of cholesterol biosynthesis enzymes in the context of HD. Therefore, we conclude that SIRT2 inhibition does not modify disease progression in the R6/2 mouse model of HD and SIRT2 inhibition should not be prioritised as a therapeutic option for HD.

Highlights

Huntington’s Disease (HD) is a devastating, autosomal dominant, neurodegenerative disorder, with a mean age of onset of 40 years [1]
Previous studies in invertebrate and cell culture models of HD have indicated that SIRT2 inhibition alters HD-related phenotypes, by modulating the expression of cholesterol biosynthesis enzymes [22,23]
To verify whether these findings could be translated to a mouse model, we investigated the effects of SIRT2 genetic reduction and depletion on HD physiological, behavioural and molecular phenotypes in the R6/2 mouse

Summary

Introduction

Huntington’s Disease (HD) is a devastating, autosomal dominant, neurodegenerative disorder, with a mean age of onset of 40 years [1]. HD symptoms are typically movement disorders, rapid weight loss, dementia and psychiatric disturbances, and the disease progresses to death over the course of 15–20 years [1,2,3]. Disturbances in many cellular processes including transcriptional regulation, synaptic function, intracellular trafficking and energy homeostasis have been observed in HD [9]. Whether these contribute to or are an effect of HD pathology is currently unclear [9]. Therapeutic options currently available to HD patients are directed against primary symptoms such as chorea or depression, these approaches do not modify disease progression and as such, have limited benefits [3]

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