title: Phosphorylation in the amino terminus of tau prevents inhibition of anterograde axonal transport.
abstract: Alzheimer's disease (AD) and other tauopathies are characterized by fibrillar inclusions composed of the microtubule-associated protein, tau. Recently, we demonstrated that the N-terminus of tau (amino acids [aa] 2-18) in filamentous aggregates or N-terminal tau isoforms activate a signaling cascade involving protein phosphatase 1 and glycogen synthase kinase 3 that results in inhibition of anterograde fast axonal transport (FAT). We have termed the functional motif comprised of aa 2-18 in tau the phosphatase-activating domain (PAD). Here, we show that phosphorylation of tau at tyrosine 18, which is a fyn phosphorylation site within PAD, prevents inhibition of anterograde FAT induced by both filamentous tau and 6D tau. Moreover, Fyn-mediated phosphorylation of tyrosine 18 is reduced in disease-associated forms of tau (e.g., tau filaments). A novel PAD-specific monoclonal antibody revealed that exposure of PAD in tau occurs before and more frequently than tyrosine 18 phosphorylation in the evolution of tangle formation in AD. These results indicate that N-terminal phosphorylation may constitute a regulatory mechanism that controls tau-mediated inhibition of anterograde FAT in AD.
authors.affiliation: Division of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Kanaan
authors.forename: Gerardo
authors.initials: G
authors.lastname: Morfini
authors.forename: Gustavo
authors.initials: G
authors.lastname: Pigino
authors.forename: Nichole E
authors.initials: NE
authors.lastname: LaPointe
authors.forename: Athena
authors.initials: A
authors.lastname: Andreadis
authors.forename: Yuyu
authors.initials: Y
authors.lastname: Song
authors.forename: Ellen
authors.initials: E
authors.lastname: Leitman
authors.forename: Lester I
authors.initials: LI
authors.lastname: Binder
authors.forename: Scott T
authors.initials: ST
authors.lastname: Brady
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000704:Analysis of Variance; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D049832:Decapodiformes; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D009154:Mutation / Q000235:genetics; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs / Q000235:genetics / Q000502:physiology*; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D020033:Protein Isoforms; D016875:tau Proteins; D014443:Tyrosine; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn