Department of Medicine, University of Cambridge, Cambridge, UK.
J Pathol. 2012 Jan;226(2):241-54. doi: 10.1002/path.3021.
With a constitutive recycling function and the capacity to digest exogenous material as well as endogenous organelles in the process of autophagy, lysosomes are at the heart of the living cell. Dynamic interactions with other cellular components ensure that the lysosomal compartment is a central point of convergence in countless diverse diseases. Inborn lysosomal (storage) diseases represent about 70 genetically distinct conditions, with a combined birth frequency of about 1 in 7500. Many are associated with macromolecular storage, causing physical disruption of the organelle and cognate structures; in neurons, ectopic dendritogenesis and axonal swelling due to distension with membraneous tubules and autophagic vacuoles are observed. Disordered autophagy is almost universal in lysosomal diseases but biochemical injury due to toxic metabolites such as lysosphingolipid molecules, abnormal calcium homeostasis and endoplasmic reticulum stress responses and immune-inflammatory processes occur. However, in no case have the mechanistic links between individual clinico-pathological manifestations and the underlying molecular defect been precisely defined. With access to the external fluid-phase and intracellular trafficking pathways, the lysosome and its diseases are a focus of pioneering investment in biotechnology; this has generated innovative orphan drugs and, in the case of Gaucher's disease, effective treatment for the haematological and visceral manifestations. Given that two-thirds of lysosomal diseases have potentially devastating consequences in the nervous system, future therapeutic research will require an integrative understanding of the unitary steps in their neuro pathogenesis. Informative genetic variants illustrated by patients with primary defects in this organelle offer unique insights into the central role of lysosomes in human health and disease. We provide a conspectus of inborn lysosomal diseases and their pathobiology; the cryptic evolution of events leading to irreversible changes may be dissociated from the cellular storage phenotype, as revealed by the outcome of therapeutic gene transfer undertaken at different stages of disease.
溶酶体具有组成性的循环功能，能够在自噬过程中消化外源性物质和内源性细胞器，是活细胞的核心。与其他细胞成分的动态相互作用确保了溶酶体隔室是无数不同疾病的集中交汇点。先天性溶酶体（储存）疾病代表了大约 70 种不同遗传的疾病，其综合出生率约为每 7500 例中有 1 例。许多疾病与大分子储存有关，导致细胞器和同源结构的物理破坏；在神经元中，由于膜性小管和自噬空泡的扩张导致异常树突生成和轴突肿胀。溶酶体疾病中几乎普遍存在无序自噬，但由于毒性代谢物（如溶脂磷脂分子）、异常钙稳态和内质网应激反应以及免疫炎症过程等原因导致的生化损伤也会发生。然而，在任何情况下，个体临床病理表现与潜在分子缺陷之间的机制联系都没有被精确定义。由于溶酶体及其疾病可以通过外部液相对象和细胞内运输途径进行研究，因此成为生物技术开创性投资的重点；这为孤儿药物的开发提供了创新思路，并且在戈谢病的情况下，为血液学和内脏表现提供了有效的治疗方法。鉴于三分之二的溶酶体疾病在神经系统中具有潜在的毁灭性后果，未来的治疗研究将需要对其神经发病机制的单一步骤进行综合理解。由该细胞器中存在原发性缺陷的患者提供的有意义的遗传变异为溶酶体在人类健康和疾病中的核心作用提供了独特的见解。我们提供了先天性溶酶体疾病及其病理生物学的概述；导致不可逆转变化的事件的隐蔽进化可能与细胞储存表型分离，这可以通过在疾病的不同阶段进行治疗性基因转移的结果来揭示。
