Morató L, Ruiz M, Boada J, Calingasan N Y, Galino J, Guilera C, Jové M, Naudí A, Ferrer I, Pamplona R, Serrano M, Portero-Otín M, Beal M F, Fourcade S, Pujol A
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Spain.
Center for Biomedical Research on Rare Diseases (CIBERER) ISCIII, Spain.
Cell Death Differ. 2015 Nov;22(11):1742-53. doi: 10.1038/cdd.2015.20. Epub 2015 Mar 27.
Oxidative stress and mitochondrial failure are prominent factors in the axonal degeneration process. In this study, we demonstrate that sirtuin 1 (SIRT1), a key regulator of the mitochondrial function, is impaired in the axonopathy and peroxisomal disease X-linked adrenoleukodystrophy (X-ALD). We have restored SIRT1 activity using a dual strategy of resveratrol treatment or by the moderate transgenic overexpression of SIRT1 in a X-ALD mouse model. Both strategies normalized redox homeostasis, mitochondrial respiration, bioenergetic failure, axonal degeneration and associated locomotor disabilities in the X-ALD mice. These results indicate that the reactivation of SIRT1 may be a valuable strategy to treat X-ALD and other axonopathies in which the control of redox and energetic homeostasis is impaired.
氧化应激和线粒体功能障碍是轴突退变过程中的突出因素。在本研究中，我们证明了线粒体功能的关键调节因子沉默调节蛋白1（SIRT1）在轴索性神经病和过氧化物酶体疾病X连锁肾上腺脑白质营养不良（X-ALD）中受损。我们通过白藜芦醇治疗的双重策略或在X-ALD小鼠模型中适度转基因过表达SIRT1来恢复SIRT1活性。两种策略均使X-ALD小鼠的氧化还原稳态、线粒体呼吸、生物能量衰竭、轴突退变及相关运动障碍恢复正常。这些结果表明，SIRT1的重新激活可能是治疗X-ALD和其他氧化还原及能量稳态控制受损的轴索性神经病的一种有价值的策略。
