Abstract
The retromer complex is a protein complex that plays a central role in endosomal trafficking. Retromer dysfunction has been linked to a growing number of neurological disorders. The process of intracellular trafficking and recycling is crucial for maintaining normal intracellular homeostasis, which is partly achieved through the activity of the retromer complex. The retromer complex plays a primary role in sorting endosomal cargo back to the cell surface for reuse, to the trans-Golgi network (TGN), or alternatively to specialized endomembrane compartments, in which the cargo is not subjected to lysosomal-mediated degradation. In most cases, the retromer acts as a core that interacts with associated proteins, including sorting nexin family member 27 (SNX27), members of the vacuolar protein sorting 10 (VPS10) receptor family, the major endosomal actin polymerization-promoting complex known as Wiskott-Aldrich syndrome protein and scar homolog (WASH), and other proteins. Some of the molecules carried by the retromer complex are risk factors for neurodegenerative diseases. Defects such as haplo-insufficiency or mutations in one or several units of the retromer complex lead to various pathologies. Here, we summarize the molecular architecture of the retromer complex and the roles of this system in intracellular trafficking related the pathogenesis of neurodegenerative diseases.
Highlights
Cargo originating from the plasma membrane (PM) and biosynthetic pathways is internalized to endosomes through endocytosis, after which cargo proteins are recruited to different destinations for many cellular activities
The results described above demonstrate that low expression levels of SORLA and SORCS1 causes pathogenic processing of amyloid precursor protein (APP) by decreasing the time that APP resides in the trans-Golgi network (TGN); we hypothesize that increasing expression of SORLA and SORCS1 or facilitating trafficking of these proteins from endosomes to the TGN might have protective effects against Alzheimer’s disease (AD)
The trend in pathophysiological research on neurodegenerative diseases is shifting from studying disease-specific, causative, misfolded proteins towards determining the pathways and protein complexes that may contribute to the pathogenesis of such diseases
Summary
National Animal Transmissible Spongiform Encephalopathy Laboratory, Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine and State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China. The retromer complex is a protein complex that plays a central role in endosomal trafficking. The retromer complex plays a primary role in sorting endosomal cargo back to the cell surface for reuse, to the trans-Golgi network (TGN), or alternatively to specialized endomembrane compartments, in which the cargo is not subjected to lysosomal-mediated degradation. Some of the molecules carried by the retromer complex are risk factors for neurodegenerative diseases. Defects such as haplo-insufficiency or mutations in one or several units of the retromer complex lead to various pathologies. We summarize the molecular architecture of the retromer complex and the roles of this system in intracellular trafficking related the pathogenesis of neurodegenerative diseases
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