Martínez-Banaclocha Marcos Arturo
Department of Pathology, Hospital Lluis Alcanyis, Xativa, Spain.
Curr Med Chem. 2017;24(3):312-330. doi: 10.2174/0929867323666161129124549.
Muscular dystrophies are inherited disorders characterized by progressive skeletal muscle degeneration without curative therapy. The specific defective protein in each type of muscular dystrophy has been associated with different deleterious factors that contribute to the progression of the disease. Among these factors, the impairment of calcium homeostasis, the ubiquitin-proteasome dysfunction, and the oxidative damage of cellular macromolecules seem to be of central importance. Can these different cellular dysfunctions be linked by a common pathogenic mechanism susceptible to therapy? A cellular cysteine network (CYSTEINET) has been proposed previously, as a matrix of interconnected sensitive cysteine-containing proteins (SCCPs) that in addition to reactive species and the cysteine/glutathione cycles can regulate metabolic, redox, and survival cellular pathways by a complex biochemical network of proteins with different functions, but sharing the same regulatory thiol group.
Since there are many sensitive cysteine-containing proteins including cysteinedependent enzymes susceptible to redox modifications at cysteine residues that may contribute to muscular degeneration, the aim of this review is to propose that cysteinet dysregulation may explain oxidative damage, calcium disturbances and ubiquitin-proteasome dysfunctions associated with muscular dystrophies.
The present review proposes that cysteinet dysregulation in muscular dystrophies may represent a common pathogenic network contributing, in association with the specific protein dysfunction, to muscular degeneration. In this context, N-acetylcysteine may have an important role in the restoration of the proposed cysteinet dysregulation associated with these heterogeneous types of diseases.
肌营养不良症是遗传性疾病，其特征为进行性骨骼肌退化，且无治愈性疗法。每种类型的肌营养不良症中特定的缺陷蛋白与导致疾病进展的不同有害因素相关。在这些因素中，钙稳态受损、泛素 - 蛋白酶体功能障碍以及细胞大分子的氧化损伤似乎至关重要。这些不同的细胞功能障碍能否通过一种易于治疗的共同致病机制联系起来？先前已提出细胞半胱氨酸网络（CYSTEINET），它是相互连接的含敏感半胱氨酸蛋白（SCCPs）的基质，除了反应性物质和半胱氨酸/谷胱甘肽循环外，还能通过具有不同功能但共享相同调节性硫醇基团的蛋白质复杂生化网络来调节代谢、氧化还原和细胞存活途径。
由于存在许多含敏感半胱氨酸的蛋白质，包括在半胱氨酸残基处易受氧化还原修饰影响的半胱氨酸依赖性酶，这些酶可能导致肌肉退化，本综述的目的是提出半胱氨酸网络失调可能解释与肌营养不良症相关的氧化损伤、钙紊乱和泛素 - 蛋白酶体功能障碍。
本综述提出，肌营养不良症中的半胱氨酸网络失调可能代表一种共同的致病网络，与特定蛋白质功能障碍一起导致肌肉退化。在此背景下，N - 乙酰半胱氨酸可能在恢复与这些异质性疾病相关的半胱氨酸网络失调方面发挥重要作用。
