Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro,", Novara, Italy.
Division of Neurology, Department of Clinic and Experimental Medicine and Surgery, Second University of Naples, Naples, Italy.
Med Res Rev. 2016 Sep;36(5):845-70. doi: 10.1002/med.21394. Epub 2016 Apr 26.
In familial neurodegenerative disorders, protein aggregates form continuously because of genetic mutations that drive the synthesis of truncated or unfolded proteins. The oxidative stress imposed by neurotransmitters and environmental neurotoxins constitutes an additional threat to the folding of the proteins and the integrity of organelle membranes in neurons. Failure in degrading such altered materials compromises the function of neurons and eventually leads to neurodegeneration. The lysosomal proteolytic enzyme Cathepsin D is the only aspartic-type protease ubiquitously expressed in all the cells of the human body, and it is expressed at high level in the brain. In general, cathepsin D mediated proteolysis is essential to neuronal cell homeostasis through the degradation of unfolded or oxidized protein aggregates delivered to lysosomes via autophagy or endocytosis. More specifically, many altered neuronal proteins that hallmark neurodegenerative diseases (e.g., the amyloid precursor, α-synuclein, and huntingtin) are physiologic substrates of cathepsin D and would abnormally accumulate if not efficiently degraded by this enzyme. Furthermore, experimental evidence indicates that cathepsin D activity is linked to the metabolism of cholesterol and of glycosaminoglycans, which accounts for its involvement in neuronal plasticity. This review focuses on the unique role of cathepsin D mediated proteolysis in the pathogenesis of human neurodegenerative diseases.
在家族性神经退行性疾病中，由于基因突变导致截断或未折叠蛋白质的合成，蛋白质聚集体不断形成。神经递质和环境神经毒素造成的氧化应激对蛋白质的折叠和神经元细胞器膜的完整性构成了另一种威胁。无法降解这些异常物质会影响神经元的功能，最终导致神经退行性变。溶酶体蛋白水解酶组织蛋白酶 D 是唯一在人体所有细胞中广泛表达的天冬氨酸蛋白酶，在大脑中表达水平较高。一般来说，组织蛋白酶 D 介导的蛋白水解通过降解通过自噬或内吞作用递送至溶酶体的未折叠或氧化的蛋白质聚集体，对神经元细胞的内稳态至关重要。更具体地说，许多改变的神经元蛋白是神经退行性疾病的标志性蛋白（例如，淀粉样前体蛋白、α-突触核蛋白和亨廷顿蛋白），是组织蛋白酶 D 的生理底物，如果不能被这种酶有效降解，就会异常积累。此外，实验证据表明，组织蛋白酶 D 活性与胆固醇和糖胺聚糖的代谢有关，这解释了其在神经元可塑性中的作用。这篇综述重点介绍了组织蛋白酶 D 介导的蛋白水解在人类神经退行性疾病发病机制中的独特作用。
