Loss of AP-5 results in accumulation of aberrant endolysosomes: defining a new type of lysosomal storage disease
Loss of AP-5 results in accumulation of aberrant endolysosomes: defining a new type of lysosomal storage disease
复制标题
DOI：
10.1093/hmg/ddv220
复制
发表时间：
2015-09-01
影响因子：
3.5
通讯作者：
Robinson, Margaret S.
中科院分区：
文献类型：
--
作者：
Hirst, Jennifer;Edgar, James R.;Robinson, Margaret S.
衔接蛋白（AP 1-5）是异四聚体复合物，在囊泡介导的运输中促进专门的货物分拣。编码AP-5复合物亚基的AP5Z1突变已被报道可导致遗传性痉挛性截瘫（HSP），尽管其在细胞水平上的影响尚未得到评估。在这里，我们描述了来自AP5Z1无义突变患者皮肤活检的三种独立成纤维细胞系，这些患者表现为痉挛性截瘫并伴有神经病变、帕金森病和/或认知障碍。在所有三个患者来源的系中，我们发现AP-5蛋白完全丢失，相关AP-5 mu -5蛋白减少。通过超微结构分析，我们发现这些患者来源的细胞系一致表现出丰富的多层结构，这些多层结构对内溶酶体标记呈阳性，并且充满异常的储存物质，组织为夸张的多层螺旋、条纹带和“指纹体”。这种表型可以通过siRNA敲低AP-5 zeta在HeLa细胞培养模型中复制。细胞表型与许多溶酶体贮积病（lsd）所描述的特征惊人地相似。总的来说，这些发现揭示了AP-5在内体和溶酶体稳态中的作用，阐明了与AP-5在神经元中的作用相关的潜在病理机制，并扩大了对隐性热休克蛋白的理解。此外，由此导致的内溶酶体储存物质的积累使我们提出AP-5缺乏症代表了一种新型的lsd。
Adaptor proteins (AP 1-5) are heterotetrameric complexes that facilitate specialized cargo sorting in vesicular-mediated trafficking. Mutations in AP5Z1, encoding a subunit of the AP-5 complex, have been reported to cause hereditary spastic paraplegia (HSP), although their impact at the cellular level has not been assessed. Here we characterize three independent fibroblast lines derived from skin biopsies of patients harbouring nonsense mutations in AP5Z1 and presenting with spastic paraplegia accompanied by neuropathy, parkinsonism and/or cognitive impairment. In all three patient-derived lines, we show that there is complete loss of AP-5 protein and a reduction in the associated AP-5 mu 5 protein. Using ultrastructural analysis, we show that these patient-derived lines consistently exhibit abundant multilamellar structures that are positive for markers of endolysosomes and are filled with aberrant storage material organized as exaggerated multilamellar whorls, striated belts and 'fingerprint bodies'. This phenotype can be replicated in a HeLa cell culture model by siRNA knockdown of AP-5 zeta. The cellular phenotype bears striking resemblance to features described in a number of lysosomal storage diseases (LSDs). Collectively, these findings reveal an emerging picture of the role of AP-5 in endosomal and lysosomal homeostasis, illuminates a potential pathomechanism that is relevant to the role of AP-5 in neurons and expands the understanding of recessive HSPs. Moreover, the resulting accumulation of storage material in endolysosomes leads us to propose that AP-5 deficiency represents a new type of LSDs.