Wang Y, MacDonald R G, Thinakaran G, Kar S
Department of Psychiatry, University of Alberta, Edmonton, AB, T6G 2M8, Canada.
Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada.
Mol Neurobiol. 2017 May;54(4):2636-2658. doi: 10.1007/s12035-016-9849-7. Epub 2016 Mar 19.
The insulin-like growth factor II/mannose 6-phosphate (IGF-II/M6P) receptor is a multifunctional single transmembrane glycoprotein. Recent studies have advanced our understanding of the structure, ligand-binding properties, and trafficking of the IGF-II/M6P receptor. This receptor has been implicated in a variety of important cellular processes including growth and development, clearance of IGF-II, proteolytic activation of enzymes, and growth factor precursors, in addition to its well-known role in the delivery of lysosomal enzymes. The IGF-II/M6P receptor, distributed widely in the central nervous system, has additional roles in mediating neurotransmitter release and memory enhancement/consolidation, possibly through activating IGF-II-related intracellular signaling pathways. Recent studies suggest that overexpression of the IGF-II/M6P receptor may have an important role in regulating the levels of transcripts and proteins involved in the development of Alzheimer's disease (AD)-the prevalent cause of dementia affecting the elderly population in our society. It is reported that IGF-II/M6P receptor overexpression can increase the levels/processing of amyloid precursor protein leading to the generation of β-amyloid peptide, which is associated with degeneration of neurons and subsequent development of AD pathology. Given the significance of the receptor in mediating the transport and functioning of the lysosomal enzymes, it is being considered for therapeutic delivery of enzymes to the lysosomes to treat lysosomal storage disorders. Notwithstanding these results, additional studies are required to validate and fully characterize the function of the IGF-II/M6P receptor in the normal brain and its involvement in various neurodegenerative disorders including AD. It is also critical to understand the interaction between the IGF-II/M6P receptor and lysosomal enzymes in neurodegenerative processes, which may shed some light on developing approaches to detect and prevent neurodegeneration through the dysfunction of the receptor and the endosomal-lysosomal system.
胰岛素样生长因子II/甘露糖6-磷酸（IGF-II/M6P）受体是一种多功能单跨膜糖蛋白。最近的研究加深了我们对IGF-II/M6P受体的结构、配体结合特性和运输的理解。除了其在溶酶体酶传递方面的众所周知的作用外，该受体还参与了多种重要的细胞过程，包括生长和发育、IGF-II的清除、酶的蛋白水解激活以及生长因子前体。IGF-II/M6P受体广泛分布于中枢神经系统，可能通过激活与IGF-II相关的细胞内信号通路，在介导神经递质释放和记忆增强/巩固方面发挥额外作用。最近的研究表明，IGF-II/M6P受体的过表达可能在调节与阿尔茨海默病（AD）——影响我们社会老年人群的痴呆症的主要病因——发展相关的转录本和蛋白质水平方面发挥重要作用。据报道，IGF-II/M6P受体的过表达会增加淀粉样前体蛋白的水平/加工，导致β-淀粉样肽的产生，这与神经元变性和随后的AD病理发展有关。鉴于该受体在介导溶酶体酶的运输和功能方面的重要性，它正被考虑用于将酶治疗性递送至溶酶体以治疗溶酶体贮积症。尽管有这些结果，但仍需要进一步的研究来验证并全面表征IGF-II/M6P受体在正常大脑中的功能及其在包括AD在内的各种神经退行性疾病中的作用。了解IGF-II/M6P受体与溶酶体酶在神经退行性过程中的相互作用也至关重要，这可能为通过受体和内体-溶酶体系统功能障碍来检测和预防神经退行性变的方法提供一些启示。
