Dysregulation of autophagy as a common mechanism in lysosomal storage diseases.
Dysregulation of autophagy as a common mechanism in lysosomal storage diseases.
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DOI：
10.1042/ebc20170055
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发表时间：
2017-12-12
影响因子：
6.4
通讯作者：
Sarkar S
中科院分区：
文献类型：
--
作者：
Seranova E;Connolly KJ;Zatyka M;Rosenstock TR;Barrett T;Tuxworth RI;Sarkar S
溶酶体在分解代谢和合成代谢过程之间起着关键作用，作为响应于多种因素（例如生长、营养物质可用性、能量状态和细胞应激源）的信号传导途径的联系。溶酶体也是用于自噬的末端降解细胞器，大分子和受损的细胞组分和细胞器通过其被降解。自噬作为一种细胞内稳态途径，对生物体生理学至关重要。衰老期间或许多疾病中自噬的下降，包括迟发性神经变性形式，被认为是病理学的主要促成因素。多种证据表明，自噬损伤也是几种溶酶体贮积症（LSD）的核心机制。LSD是一类罕见的遗传性疾病，其组织病理学标志是由于溶酶体功能异常导致的未降解物质在溶酶体中蓄积。溶酶体降解能力不足对自噬途径的通量产生负面影响，因此LSD中失调的自噬正在成为一种相关的疾病机制。LSD的病理学通常是早发性的，严重的和限制生命的，但目前的治疗方法是有限的或不存在的;认识到LSD中常见的自噬缺陷为治疗带来了新的可能性。在这篇综述中，我们描述了LSDs发生的机制，重点是自噬途径的扰动，并提出了最新的数据支持与自噬调节相关的新治疗方法的发展。
The lysosome plays a pivotal role between catabolic and anabolic processes as the nexus for signalling pathways responsive to a variety of factors, such as growth, nutrient availability, energetic status and cellular stressors. Lysosomes are also the terminal degradative organelles for autophagy through which macromolecules and damaged cellular components and organelles are degraded. Autophagy acts as a cellular homeostatic pathway that is essential for organismal physiology. Decline in autophagy during ageing or in many diseases, including late-onset forms of neurodegeneration is considered a major contributing factor to the pathology. Multiple lines of evidence indicate that impairment in autophagy is also a central mechanism underlying several lysosomal storage disorders (LSDs). LSDs are a class of rare, inherited disorders whose histopathological hallmark is the accumulation of undegraded materials in the lysosomes due to abnormal lysosomal function. Inefficient degradative capability of the lysosomes has negative impact on the flux through the autophagic pathway, and therefore dysregulated autophagy in LSDs is emerging as a relevant disease mechanism. Pathology in the LSDs is generally early-onset, severe and life-limiting but current therapies are limited or absent; recognizing common autophagy defects in the LSDs raises new possibilities for therapy. In this review, we describe the mechanisms by which LSDs occur, focusing on perturbations in the autophagy pathway and present the latest data supporting the development of novel therapeutic approaches related to the modulation of autophagy.