Molecular Basis of Orb2 Amyloidogenesis and Blockade of Memory Consolidation

PLoS Biol. 2016 Jan 26;14(1):e1002361. doi: 10.1371/journal.pbio.1002361. eCollection 2016 Jan.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloidogenic Proteins / metabolism*
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Drosophila Proteins / chemistry
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster
  • Female
  • Male
  • Memory Consolidation*
  • Mutation
  • Oligopeptides
  • Protein Structure, Tertiary
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Yeasts
  • mRNA Cleavage and Polyadenylation Factors / chemistry
  • mRNA Cleavage and Polyadenylation Factors / genetics
  • mRNA Cleavage and Polyadenylation Factors / metabolism*

Substances

  • Amyloidogenic Proteins
  • Drosophila Proteins
  • Oligopeptides
  • Orb2 protein, Drosophila
  • Transcription Factors
  • mRNA Cleavage and Polyadenylation Factors
  • polyglutamine-binding protein 1

Grant support

This research was supported by funds from SAF2013-49179-C2-1-R JPND_CD_FP-688-059 (AC14/00037 ISCIII) to MCV, SIMR to KS, SAF2013-49179-C2-2-R JPND_CD_FP-688-059 (AC14/00037 ISCIII) to DVL, BFU2012-36825, S2011/BMD-2457 (Comunidad de Madrid), Centro de Investigación Biomédica en Red sobre Enfermedades Respiratorias (CIBERES) to MM, CTQ2011-22514 to MB, Core Research for Evolutional Science and Technology (CREST) from the Japan Science and Technology Agency, Grants-in-Aid for Scientific Research on Innovative Areas (Synapse and Neurocircuit Pathology) from the Ministry of Education, Culture, Sports, Science, and Technology, Health Labour Sciences Research Grant for Research on Intractable Diseases from the Ministry of Health, Labour and Welfare, Japan to YN and a Ramon y Cajal contract from MICINN to SCT. The following fellowships were involved: Fundación Ferrer (Severo Ochoa fellowship) and Canon Foundation to RH, SIMR to LY and AM, MECD to AGP, MINECO to ES, and Japan Intractable Disease Research Foundation to MS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.