Division of Pediatric Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
Department of Neurology, Harvard Medical School, Boston Children's Hospital, 3 Blackfan Circle, CLS 14060, Boston, MA, 02115, USA.
J Inherit Metab Dis. 2017 Sep;40(5):631-640. doi: 10.1007/s10545-017-0048-0. Epub 2017 May 5.
Lysosomal storage diseases (LSD) are inborn errors of metabolism resulting in multisystem disease. Central nervous system involvement, often with progressive neurodegeneration, accounts for a large portion of the morbidity and mortality seen in many LSD. Available treatments fail to prevent or correct neurologic symptoms and decline. Emerging evidence points to an important role for mitochondrial dysfunction in the pathogenesis and progression of LSD-associated neurodegeneration. Mitochondrial dysfunction in LSD is characterized by alterations in mitochondrial mass, morphology and function. Disturbed mitochondrial metabolism in the CNS may lead to excessive production of mitochondrial reactive oxygen species and dysregulated calcium homeostasis. These metabolic disturbances ultimately result in mitochondria-induced apoptosis and neuronal degeneration. Here, we review the current evidence for mitochondrial dysfunction in neuronal models of seven LSD, including GM1-gangliosidosis, mucopolysaccharidosis IIIC, multiple sulfatase deficiency, Krabbe disease, Gaucher disease, Niemann Pick disease type C and the neural ceroid lipofuscinoses and outline current experimental therapies aimed at restoring mitochondrial function and neuroprotection in LSD.
溶酶体贮积症（LSD）是一种代谢性遗传病，可导致多系统疾病。中枢神经系统受累，常伴有进行性神经退行性变，是许多 LSD 患者发病率和死亡率高的主要原因。现有的治疗方法未能预防或纠正神经症状和疾病进展。新出现的证据表明，线粒体功能障碍在 LSD 相关神经退行性变的发病机制和进展中起着重要作用。 LSD 中的线粒体功能障碍的特征是线粒体质量、形态和功能的改变。中枢神经系统中线粒体代谢紊乱可能导致线粒体活性氧的过度产生和钙稳态失调。这些代谢紊乱最终导致线粒体诱导的细胞凋亡和神经元变性。在这里，我们回顾了七种 LSD 的神经元模型中线粒体功能障碍的现有证据，包括 GM1-神经节苷脂贮积症、黏多糖贮积症 III 型、多种硫酸酯酶缺乏症、克拉伯病、戈谢氏病、尼曼-皮克病 C 型和神经鞘脂褐质沉积症，并概述了目前旨在恢复 LSD 中线粒体功能和神经保护的实验性治疗方法。
