Article

Aplysia CPEB Can Form Prion-like Multimers in Sensory Neurons that Contribute to Long-Term Facilitation

Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.
Cell (Impact Factor: 32.24). 02/2010; 140(3):421-35. DOI: 10.1016/j.cell.2010.01.008
Source: PubMed

ABSTRACT

Prions are proteins that can assume at least two distinct conformational states, one of which is dominant and self-perpetuating. Previously we found that a translation regulator CPEB from Aplysia, ApCPEB, that stabilizes activity-dependent changes in synaptic efficacy can display prion-like properties in yeast. Here we find that, when exogenously expressed in sensory neurons, ApCPEB can form an amyloidogenic self-sustaining multimer, consistent with it being a prion-like protein. In addition, we find that conversion of both the exogenous and the endogenous ApCPEB to the multimeric state is enhanced by the neurotransmitter serotonin and that an antibody that recognizes preferentially the multimeric ApCPEB blocks persistence of synaptic facilitation. These results are consistent with the idea that ApCPEB can act as a self-sustaining prion-like protein in the nervous system and thereby might allow the activity-dependent change in synaptic efficacy to persist for long periods of time.

Full-text preview

Available from: bcm.edu
  • Source
    • "Putative prion domains from other Saccharomycetes (but not from fungal clades outside of this one) can make prions in S. cerevisiae or in their own cells, although this ability is sporadic252627282930, and can rely on small changes in the protein sequence[29]. Conversely, the full-length non-yeast protein CPEB from the sea hare Aplysia californica can form prions in S. cerevisiae, albeit with much less efficiency than native prions[31,32]. Mutational experiments indicate that many N/Qrich domains in S. cerevisiae may only be a small number of sequence mutations away from prion-forming ability, implying that natural selection may only act to keep aggregation propensities sufficiently low[33]; this may be an under-appreciated effect in the analysis of mammalian prion disease mutations[34,35]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Prions are transmissible, propagating alternative states of proteins, and are usually made from the fibrillar, beta-sheet-rich assemblies termed amyloid. Prions in the budding yeast Saccharomyces cerevisiae propagate heritable phenotypes, uncover hidden genetic variation, function in large-scale gene regulation, and can act like diseases. Almost all these amyloid prions have asparagine/glutamine-rich (N/Q–rich) domains. Other proteins, that we term here ‘prionogenic amyloid formers’ (PAFs), have been shown to form amyloid in vivo, and to have N/Q-rich domains that can propagate heritable states in yeast cells. Also, there are >200 other S.cerevisiae proteins with prion-like N/Q-rich sequence composition. Furthermore, human proteins with such N/Q-rich composition have been linked to the pathomechanisms of neurodegenerative amyloid diseases. Results Here, we exploit the increasing abundance of complete fungal genomes to examine the ancestry of prions/PAFs and other N/Q-rich proteins across the fungal kingdom. We find distinct evolutionary behavior for Q-rich and N-rich prions/PAFs; those of ancient ancestry (outside the budding yeasts, Saccharomycetes) are Q-rich, whereas N-rich cases arose early in Saccharomycetes evolution. This emergence of N-rich prion/PAFs is linked to a large-scale emergence of N-rich proteins during Saccharomycetes evolution, with Saccharomycetes showing a distinctive trend for population sizes of prion-like proteins that sets them apart from all the other fungi. Conversely, some clades, e.g. Eurotiales, have much fewer N/Q-rich proteins, and in some cases likely lose them en masse, perhaps due to greater amyloid intolerance, although they contain relatively more non-N/Q-rich predicted prions. We find that recent mutational tendencies arising during Saccharomycetes evolution (i.e., increased numbers of N residues and a tendency to form more poly-N tracts), contributed to the expansion/development of the prion phenomenon. Variation in these mutational tendencies in Saccharomycetes is correlated with the population sizes of prion-like proteins, thus implying that selection pressures on N/Q-rich protein sequences against amyloidogenesis are not generally maintained in budding yeasts. Conclusions These results help to delineate further the limits and origins of N/Q-rich prions, and provide insight as a case study of the evolution of compositionally-defined protein domains. Electronic supplementary material The online version of this article (doi:10.1186/s12862-016-0594-3) contains supplementary material, which is available to authorized users.
    Full-text · Article · Dec 2016 · BMC Evolutionary Biology
  • Source
    • "Defects or polyglutamine (polyQ) expansions in some RNA regulators can induce large solid aggregates, which are common in central nervous system (CNS) diseases (King et al., 2012; Ramaswami et al., 2013). In the normal CNS, prion-like (solid) RNP polymers may contribute to long-term potentiation (Si et al., 2010; Heinrich and Lindquist, 2011). Collectively, these findings suggest that RNP condensations are carefully regulated, influencing RNP dynamics and fate. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Ribonucleoproteins (RNPs) often coassemble into supramolecular bodies with regulated dynamics. The factors controlling RNP bodies and connections to RNA regulation are unclear. During Caenorhabditis elegans oogenesis, cytoplasmic RNPs can transition among diffuse, liquid, and solid states linked to mRNA regulation. Loss of CGH-1/Ddx6 RNA helicase generates solid granules that are sensitive to mRNA regulators. Here, we identified 66 modifiers of RNP solids induced by cgh-1 mutation. A majority of genes promote or suppress normal RNP body assembly, dynamics, or metabolism. Surprisingly, polyadenylation factors promote RNP coassembly in vivo, suggesting new functions of poly(A) tail regulation in RNP dynamics. Many genes carry polyglutatmine (polyQ) motifs or modulate polyQ aggregation, indicating possible connections with neurodegenerative disorders induced by CAG/polyQ expansion. Several RNP body regulators repress translation of mRNA subsets, suggesting that mRNAs are repressed by multiple mechanisms. Collectively, these findings suggest new pathways of RNP modification that control large-scale coassembly and mRNA activity during development.
    Preview · Article · Nov 2015 · The Journal of Cell Biology
  • Source
    • "According to the neuro-physiological studies by Si et al. (2010) and Majumdar et al. (2012), most of the memory is short-term. The main memory element – a neuron – has a great number of synapses (about 3 10 synapses per neuron) and can possess a plurality of states. "
    [Show description] [Hide description]
    DESCRIPTION: Three laws of knowledge production explaining the empirically observed hyperbolic growth of world population are formulated. Knowledge and demographic dynamics are developed on the basis of the least action principle to describe deviations from the hyperbolic growth. The efficiency of knowledge production defined as the share of technological knowledge in total knowledge production is introduced. It is proved that monotonic population growth with reaching a plateau is possible only when efficiency is 1. At a lower efficiency, population reaches a maximum and then declines. The estimated efficiency is currently not more than 0.1. The calculations show that if efficiency remains constant, population will peak at 9 billion in the mid-21st century and then decline to 5 billion or lower over several centuries. To keep population at a level of not less than 90% of maximum, it is necessary to raise efficiency of up to 0.31.
    Full-text · Research · Jul 2015
Show more