title: Molecular Basis of Orb2 Amyloidogenesis and Blockade of Memory Consolidation.
abstract: Amyloids are ordered protein aggregates that are typically associated with neurodegenerative diseases and cognitive impairment. By contrast, the amyloid-like state of the neuronal RNA binding protein Orb2 in Drosophila was recently implicated in memory consolidation, but it remains unclear what features of this functional amyloid-like protein give rise to such diametrically opposed behaviour. Here, using an array of biophysical, cell biological and behavioural assays we have characterized the structural features of Orb2 from the monomer to the amyloid state. Surprisingly, we find that Orb2 shares many structural traits with pathological amyloids, including the intermediate toxic oligomeric species, which can be sequestered in vivo in hetero-oligomers by pathological amyloids. However, unlike pathological amyloids, Orb2 rapidly forms amyloids and its toxic intermediates are extremely transient, indicating that kinetic parameters differentiate this functional amyloid from pathological amyloids. We also observed that a well-known anti-amyloidogenic peptide interferes with long-term memory in Drosophila. These results provide structural insights into how the amyloid-like state of the Orb2 protein can stabilize memory and be nontoxic. They also provide insight into how amyloid-based diseases may affect memory processes.
authors.affiliation: Instituto Cajal, IC-CSIC, Madrid, Spain.|Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA-Nanociencia), Madrid, Spain.
authors.forename: Rubén
authors.initials: R
authors.lastname: Hervás
authors.affiliation: Stowers Institute for Medical Research, Kansas City, Missouri, United States of America.|Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, United States of America.
authors.forename: Liying
authors.initials: L
authors.lastname: Li
authors.affiliation: Stowers Institute for Medical Research, Kansas City, Missouri, United States of America.|National Brain Research Centre, Manesar, Guragon, Haryana, India.
authors.forename: Amitabha
authors.initials: A
authors.lastname: Majumdar
authors.affiliation: Instituto Cajal, IC-CSIC, Madrid, Spain.|Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA-Nanociencia), Madrid, Spain.
authors.forename: María Del Carmen
authors.initials: Mdel C
authors.lastname: Fernández-Ramírez
authors.affiliation: Stowers Institute for Medical Research, Kansas City, Missouri, United States of America.
authors.forename: Jay R
authors.initials: JR
authors.lastname: Unruh
authors.affiliation: Stowers Institute for Medical Research, Kansas City, Missouri, United States of America.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Slaughter
authors.affiliation: Instituto Cajal, IC-CSIC, Madrid, Spain.|Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA-Nanociencia), Madrid, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Galera-Prat
authors.affiliation: Instituto Cajal, IC-CSIC, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Santana
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.|Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Nagai
authors.affiliation: Instituto de Química-Física Rocasolano, IQFR-CSIC, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Bruix
authors.affiliation: Instituto Cajal, IC-CSIC, Madrid, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Casas-Tintó
authors.affiliation: Instituto de Química-Física Rocasolano, IQFR-CSIC, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Respiratorias, Madrid, Spain.
authors.forename: Margarita
authors.initials: M
authors.lastname: Menéndez
authors.affiliation: Instituto de Química-Física Rocasolano, IQFR-CSIC, Madrid, Spain.
authors.forename: Douglas V
authors.initials: DV
authors.lastname: Laurents
authors.affiliation: Stowers Institute for Medical Research, Kansas City, Missouri, United States of America.|Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, United States of America.
authors.forename: Kausik
authors.initials: K
authors.lastname: Si
authors.affiliation: Instituto Cajal, IC-CSIC, Madrid, Spain.|Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA-Nanociencia), Madrid, Spain.
authors.forename: Mariano
authors.initials: M
authors.lastname: Carrión-Vázquez
mesh_terms: D058227:Amyloidogenic Proteins / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D005260:Female; D008297:Male; D000069077:Memory Consolidation; D009154:Mutation; D009842:Oligopeptides; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015003:Yeasts; D039221:mRNA Cleavage and Polyadenylation Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D058227:Amyloidogenic Proteins; D029721:Drosophila Proteins; D009842:Oligopeptides; C529066:Orb2 protein, Drosophila; D014157:Transcription Factors; D039221:mRNA Cleavage and Polyadenylation Factors; C407346:polyglutamine-binding protein 1
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