Cargando…

An ancient conserved role for prion protein in learning and memory

The misfolding of cellular prion protein (PrP(C)) to form PrP Scrapie (PrP(Sc)) is an exemplar of toxic gain-of-function mechanisms inducing propagated protein misfolding and progressive devastating neurodegeneration. Despite this, PrP(C) function in the brain is also reduced and subverted during pr...

Descripción completa

Detalles Bibliográficos
Autores principales: Leighton, Patricia L. A., Nadolski, Nathan J., Morrill, Adam, Hamilton, Trevor J., Allison, W. Ted
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829491/
https://www.ncbi.nlm.nih.gov/pubmed/29358166
http://dx.doi.org/10.1242/bio.025734
_version_ 1783302814769872896
author Leighton, Patricia L. A.
Nadolski, Nathan J.
Morrill, Adam
Hamilton, Trevor J.
Allison, W. Ted
author_facet Leighton, Patricia L. A.
Nadolski, Nathan J.
Morrill, Adam
Hamilton, Trevor J.
Allison, W. Ted
author_sort Leighton, Patricia L. A.
collection PubMed
description The misfolding of cellular prion protein (PrP(C)) to form PrP Scrapie (PrP(Sc)) is an exemplar of toxic gain-of-function mechanisms inducing propagated protein misfolding and progressive devastating neurodegeneration. Despite this, PrP(C) function in the brain is also reduced and subverted during prion disease progression; thus understanding the normal function of PrP(C) in healthy brains is key. Disrupting PrP(C) in mice has led to a myriad of controversial functions that sometimes map onto disease symptoms, including a proposed role in memory or learning. Intriguingly, PrP(C) interaction with amyloid beta (Aβ) oligomers at synapses has also linked its function to Alzheimer's disease and dementia in recent years. We set out to test the involvement of PrP(C) in memory using a disparate animal model, the zebrafish. Here we document an age-dependent memory decline in prp2(−/−) zebrafish, pointing to a conserved and ancient role of PrP(C) in memory. Specifically, we found that aged (3-year-old) prp2(−/−) fish performed poorly in an object recognition task relative to age-matched prp2(+/+) fish or 1-year-old prp2(−/−) fish. Further, using a novel object approach (NOA) test, we found that aged (3-year-old) prp2(−/−) fish approached the novel object more than either age-matched prp2(+/+) fish or 1-year-old prp2(−/−) fish, but did not have decreased anxiety when we tested them in a novel tank diving test. Taken together, the results of the NOA and novel tank diving tests suggest an altered cognitive appraisal of the novel object in the 3-year-old prp2(−/−) fish. The learning paradigm established here enables a path forward to study PrP(C) interactions of relevance to Alzheimer's disease and prion diseases, and to screen for candidate therapeutics for these diseases. The findings underpin a need to consider the relative contributions of loss- versus gain-of-function of PrP(C) during Alzheimer's and prion diseases, and have implications upon the prospects of several promising therapeutic strategies.
format Online
Article
Text
id pubmed-5829491
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher The Company of Biologists Ltd
record_format MEDLINE/PubMed
spelling pubmed-58294912018-02-28 An ancient conserved role for prion protein in learning and memory Leighton, Patricia L. A. Nadolski, Nathan J. Morrill, Adam Hamilton, Trevor J. Allison, W. Ted Biol Open Research Article The misfolding of cellular prion protein (PrP(C)) to form PrP Scrapie (PrP(Sc)) is an exemplar of toxic gain-of-function mechanisms inducing propagated protein misfolding and progressive devastating neurodegeneration. Despite this, PrP(C) function in the brain is also reduced and subverted during prion disease progression; thus understanding the normal function of PrP(C) in healthy brains is key. Disrupting PrP(C) in mice has led to a myriad of controversial functions that sometimes map onto disease symptoms, including a proposed role in memory or learning. Intriguingly, PrP(C) interaction with amyloid beta (Aβ) oligomers at synapses has also linked its function to Alzheimer's disease and dementia in recent years. We set out to test the involvement of PrP(C) in memory using a disparate animal model, the zebrafish. Here we document an age-dependent memory decline in prp2(−/−) zebrafish, pointing to a conserved and ancient role of PrP(C) in memory. Specifically, we found that aged (3-year-old) prp2(−/−) fish performed poorly in an object recognition task relative to age-matched prp2(+/+) fish or 1-year-old prp2(−/−) fish. Further, using a novel object approach (NOA) test, we found that aged (3-year-old) prp2(−/−) fish approached the novel object more than either age-matched prp2(+/+) fish or 1-year-old prp2(−/−) fish, but did not have decreased anxiety when we tested them in a novel tank diving test. Taken together, the results of the NOA and novel tank diving tests suggest an altered cognitive appraisal of the novel object in the 3-year-old prp2(−/−) fish. The learning paradigm established here enables a path forward to study PrP(C) interactions of relevance to Alzheimer's disease and prion diseases, and to screen for candidate therapeutics for these diseases. The findings underpin a need to consider the relative contributions of loss- versus gain-of-function of PrP(C) during Alzheimer's and prion diseases, and have implications upon the prospects of several promising therapeutic strategies. The Company of Biologists Ltd 2018-01-10 /pmc/articles/PMC5829491/ /pubmed/29358166 http://dx.doi.org/10.1242/bio.025734 Text en © 2018. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Leighton, Patricia L. A.
Nadolski, Nathan J.
Morrill, Adam
Hamilton, Trevor J.
Allison, W. Ted
An ancient conserved role for prion protein in learning and memory
title An ancient conserved role for prion protein in learning and memory
title_full An ancient conserved role for prion protein in learning and memory
title_fullStr An ancient conserved role for prion protein in learning and memory
title_full_unstemmed An ancient conserved role for prion protein in learning and memory
title_short An ancient conserved role for prion protein in learning and memory
title_sort ancient conserved role for prion protein in learning and memory
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829491/
https://www.ncbi.nlm.nih.gov/pubmed/29358166
http://dx.doi.org/10.1242/bio.025734
work_keys_str_mv AT leightonpatriciala anancientconservedroleforprionproteininlearningandmemory
AT nadolskinathanj anancientconservedroleforprionproteininlearningandmemory
AT morrilladam anancientconservedroleforprionproteininlearningandmemory
AT hamiltontrevorj anancientconservedroleforprionproteininlearningandmemory
AT allisonwted anancientconservedroleforprionproteininlearningandmemory
AT leightonpatriciala ancientconservedroleforprionproteininlearningandmemory
AT nadolskinathanj ancientconservedroleforprionproteininlearningandmemory
AT morrilladam ancientconservedroleforprionproteininlearningandmemory
AT hamiltontrevorj ancientconservedroleforprionproteininlearningandmemory
AT allisonwted ancientconservedroleforprionproteininlearningandmemory