Arylsulfatase K inactivation causes mucopolysaccharidosis due to deficient glucuronate desulfation of heparan and chondroitin sulfate.
Arylsulfatase K inactivation causes mucopolysaccharidosis due to deficient glucuronate desulfation of heparan and chondroitin sulfate.
复制标题
DOI：
10.1042/bcj20200546
复制
发表时间：
2020-09-18
期刊：
影响因子：
--
通讯作者：
Dierks T
中科院分区：
文献类型：
--
作者：
Trabszo C;Ramms B;Chopra P;Lüllmann-Rauch R;Stroobants S;Sproß J;Jeschke A;Schinke T;Boons GJ;Esko JD;Lübke T;Dierks T
粘多糖病是一组罕见的代谢疾病，其中糖胺聚糖 (GAG) 的溶酶体降解因参与 GAG 分解代谢的溶酶体酶的遗传缺陷而受损。由此产生的 GAG 衍生代谢物在溶酶体内积累，从而表现为神经系统症状以及肝、肾、脾和骨等各种组织的外周异常。由于每个 GAG 由不同的硫酸化二糖单元组成，因此它需要一组特定但部分重叠的溶酶体酶来完成其完全降解。最近，我们鉴定并表征了溶酶体酶芳基硫酸酯酶 K (Arsk)，其具有降解硫酸乙酰肝素 (HS)、硫酸软骨素 (CS) 和硫酸皮肤素 (DS) 所需的葡萄糖醛酸-2-硫酸酯酶活性。在本研究中，我们通过组成型 Arsk 敲除小鼠模型研究了 Arsk 的生理相关性。通过特定的酶活性测定证明完全缺乏葡萄糖醛酸脱硫。 Arsk 缺陷小鼠以器官特异性方式表现出 HS 和 CS 代谢物的中等积累，其特征是非还原端有 2-O-硫酸化葡萄糖醛酸部分。病理生理学研究反映了相当温和的表型，包括行为变化。有趣的是，没有检测到明显的溶酶体储存病理学，如骨异常。我们的 Arsk 小鼠模型结果表明存在一种新的温和形式的粘多糖 (MPS)，我们将其命名为 IIB 型 MPS。
Mucopolysaccharidoses comprise a group of rare metabolic diseases, in which the lysosomal degradation of glycosaminoglycans (GAGs) is impaired due to genetically inherited defects of lysosomal enzymes involved in GAG catabolism. The resulting intralysosomal accumulation of GAG-derived metabolites consequently manifests in neurological symptoms and also peripheral abnormalities in various tissues like liver, kidney, spleen and bone. As each GAG consists of differently sulfated disaccharide units, it needs a specific, but also partly overlapping set of lysosomal enzymes to accomplish their complete degradation. Recently, we identified and characterized the lysosomal enzyme arylsulfatase K (Arsk) exhibiting glucuronate-2-sulfatase activity as needed for the degradation of heparan sulfate (HS), chondroitin sulfate (CS) and dermatan sulfate (DS). In the present study, we investigated the physiological relevance of Arsk by means of a constitutive Arsk knockout mouse model. A complete lack of glucuronate desulfation was demonstrated by a specific enzyme activity assay. Arsk-deficient mice show, in an organ-specific manner, a moderate accumulation of HS and CS metabolites characterized by 2-O-sulfated glucuronate moieties at their non-reducing ends. Pathophysiological studies reflect a rather mild phenotype including behavioral changes. Interestingly, no prominent lysosomal storage pathology like bone abnormalities were detected. Our results from the Arsk mouse model suggest a new although mild form of mucopolysacharidose (MPS), which we designate MPS type IIB.