Nicotinamide Pathway-Dependent Sirt1 Activation Restores Calcium Homeostasis to Achieve Neuroprotection in Spinocerebellar Ataxia Type 7.,Neuron

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Nicotinamide Pathway-Dependent Sirt1 Activation Restores Calcium Homeostasis to Achieve Neuroprotection in Spinocerebellar Ataxia Type 7.
Neuron ( IF 16.2 ) Pub Date : 2019-12-16 , DOI: 10.1016/j.neuron.2019.11.019
Colleen A Stoyas ₁ , David D Bushart ₂ , Pawel M Switonski ₃ , Jacqueline M Ward ₄ , Akshay Alaghatta ₁ , Mi-Bo Tang ₅ , Chenchen Niu ₁ , Mandheer Wadhwa ₁ , Haoran Huang ₆ , Alex Savchenko ₄ , Karim Gariani ₇ , Fang Xie ₄ , Joseph R Delaney ₁ , Terry Gaasterland ₈ , Johan Auwerx ₇ , Vikram G Shakkottai ₂ , Albert R La Spada ₉

Affiliation

Department of Neurology, Duke University School of Medicine, Durham, NC 27710, USA.
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Neurology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Molecular Biomedicine, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14 Str., 61-704 Poznan, Poland.
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Neurology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Neurology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000 Henan, China.
Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Neurology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Neurobiology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA; Duke Center for Neurodegeneration and Neurotherapeutics, Duke University School of Medicine, Durham, NC 27710, USA.

Sirtuin 1 (Sirt1) is a NAD+-dependent deacetylase capable of countering age-related neurodegeneration, but the basis of Sirt1 neuroprotection remains elusive. Spinocerebellar ataxia type 7 (SCA7) is an inherited CAG-polyglutamine repeat disorder. Transcriptome analysis of SCA7 mice revealed downregulation of calcium flux genes accompanied by abnormal calcium-dependent cerebellar membrane excitability. Transcription-factor binding-site analysis of downregulated genes yielded Sirt1 target sites, and we observed reduced Sirt1 activity in the SCA7 mouse cerebellum with NAD+ depletion. SCA7 patients displayed increased poly(ADP-ribose) in cerebellar neurons, supporting poly(ADP-ribose) polymerase-1 upregulation. We crossed Sirt1-overexpressing mice with SCA7 mice and noted rescue of neurodegeneration and calcium flux defects. NAD+ repletion via nicotinamide riboside ameliorated disease phenotypes in SCA7 mice and patient stem cell-derived neurons. Sirt1 thus achieves neuroprotection by promoting calcium regulation, and NAD+ dysregulation underlies Sirt1 dysfunction in SCA7, indicating that cerebellar ataxias exhibit altered calcium homeostasis because of metabolic dysregulation, suggesting shared therapy targets.

中文翻译：

烟酰胺途径依赖性Sirt1激活可恢复钙稳态，从而实现7型脊髓小脑共济失调的神经保护作用。

Sirtuin 1（Sirt1）是一种NAD +依赖性脱乙酰基酶，能够对抗与年龄相关的神经变性，但Sirt1神经保护的基础仍然难以捉摸。脊髓小脑共济失调7型（SCA7）是一种遗传性CAG-聚谷氨酰胺重复性疾病。SCA7小鼠的转录组分析显示钙通量基因下调，并伴有异常的钙依赖性小脑膜兴奋性。转录因子结合位点分析的下调基因产生Sirt1目标位点，并且我们观察到在NAD +耗竭下SCA7小鼠小脑中Sirt1活性降低。SCA7患者显示小脑神经元中的聚（ADP-核糖）增加，支持聚（ADP-核糖）聚合酶-1上调。我们将过量表达Sirt1的小鼠与SCA7小鼠杂交，并注意到神经变性和钙通量缺陷得到了挽救。通过烟酰胺核苷的NAD +补充改善了SCA7小鼠和患者干细胞来源的神经元的疾病表型。因此，Sirt1通过促进钙调节来实现神经保护作用，而NAD +调节异常是SCA7中Sirt1功能障碍的基础，这表明小脑共济失调由于代谢异常而表现出钙稳态的改变，这提示了共同的治疗目标。

更新日期：2019-12-17

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