title: NCAM1 Polysialylation: The Prion Protein's Elusive Reason for Being?
abstract: Much confusion surrounds the physiological function of the cellular prion protein (PrPC). It is, however, anticipated that knowledge of its function will shed light on its contribution to neurodegenerative diseases and suggest ways to interfere with the cellular toxicity central to them. Consequently, efforts to elucidate its function have been all but exhaustive. Building on earlier work that uncovered the evolutionary descent of the prion founder gene from an ancestral ZIP zinc transporter, we recently investigated a possible role of PrPCin a morphogenetic program referred to as epithelial-to-mesenchymal transition (EMT). By capitalizing on PrPCknockout cell clones in a mammalian cell model of EMT and using a comparative proteomics discovery strategy, neural cell adhesion molecule-1 emerged as a protein whose upregulation during EMT was perturbed in PrPCknockout cells. Follow-up work led us to observe that PrPCregulates the polysialylation of the neural cell adhesion molecule NCAM1 in cells undergoing morphogenetic reprogramming. In addition to governing cellular migration, polysialylation modulates several other cellular plasticity programs PrPChas been phenotypically linked to. These include neurogenesis in the subventricular zone, controlled mossy fiber sprouting and trimming in the hippocampal formation, hematopoietic stem cell renewal, myelin repair and maintenance, integrity of the circadian rhythm, and glutamatergic signaling. This review revisits this body of literature and attempts to present it in light of this novel contextual framework. When approached in this manner, a coherent model of PrPCacting as a regulator of polysialylation during specific cell and tissue morphogenesis events comes into focus.
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Mohadeseh
authors.initials: M
authors.lastname: Mehrabian
authors.affiliation: Institute for Cellular Chemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Hildebrandt
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada g.schmittulms@utoronto.ca.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Gerold
authors.initials: G
authors.lastname: Schmitt-Ulms
mesh_terms: D000818:Animals; D019002:CD56 Antigen / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D055495:Neurogenesis; D000072002:Prion Proteins / Q000235:genetics / Q000378:metabolism*; D060066:Protein Interaction Maps; D012794:Sialic Acids / Q000378:metabolism; D012799:Sialyltransferases / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D019002:CD56 Antigen; C522918:NCAM1 protein, human; D000072002:Prion Proteins; D012794:Sialic Acids; C021319:polysialic acid; C046778:CMP-N-acetylneuraminate-poly-alpha-2,8-sialosyl sialyltransferase; D012799:Sialyltransferases
keywords: neural cell adhesion molecules; polysialic acid; polysialyltransferases; prion protein; protein function; signaling