Insulin-Like Growth Factor-II/Cation-Independent Mannose 6-Phosphate Receptor in Neurodegenerative Diseases

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.