title: The use of pharmacological retromer chaperones in Alzheimer's disease and other endosomal-related disorders.
abstract: The retromer is an evolutionary conserved multiprotein complex involved in the sorting and retrograde trafficking of cargo from endosomal compartments to the Golgi network and to the cell surface. The neuronal retromer traffics the amyloid precursor protein away from the endosomes, a site where amyloid precursor protein is enzymatically cleaved into pathogenic fragments in Alzheimer's disease. In recent years, deficiencies in retromer-mediated transport have been implicated in several neurological and non-neurological diseases, including Parkinson's disease, suggesting that improving the efficacy of the retromer trafficking pathway would result in decreased pathology. We recently identified a new family of small molecules that appear to stabilize the interaction between members of the retromer complex and enhance its function in neurons: the retromer pharmacological chaperones. Here we discuss the role of these molecules in the improvement of retromer trafficking and endosomal dysfunction, as well as their potential as therapeutics for neurological and non-neurological disorders.
authors.affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, and Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY, 10032, USA, db2146@cumc.columbia.edu.
authors.forename: Diego E
authors.initials: DE
authors.lastname: Berman
authors.forename: Dagmar
authors.initials: D
authors.lastname: Ringe
authors.forename: Greg A
authors.initials: GA
authors.lastname: Petsko
authors.forename: Scott A
authors.initials: SA
authors.lastname: Small
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D011992:Endosomes / Q000473:pathology*; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology
chemical_list: D046912:Multiprotein Complexes; D018696:Neuroprotective Agents