Localization of mutant ubiquitin in the brain of a transgenic mouse line with proteasomal inhibition and its validation at specific sites in Alzheimer's disease
Identifieur interne : 000976 ( Pmc/Curation ); précédent : 000975; suivant : 000977Localization of mutant ubiquitin in the brain of a transgenic mouse line with proteasomal inhibition and its validation at specific sites in Alzheimer's disease
Auteurs : Romina J. G. Gentier [Pays-Bas] ; Bert M. Verheijen [Pays-Bas] ; Margherita Zamboni [Pays-Bas] ; Maartje M. A. Stroeken [Pays-Bas] ; Denise J. H. P. Hermes [Pays-Bas] ; Benno Küsters [Pays-Bas] ; Harry W. M. Steinbusch [Pays-Bas] ; David A. Hopkins [Pays-Bas, Canada] ; Fred W. Van Leeuwen [Pays-Bas]Source :
- Frontiers in Neuroanatomy [ 1662-5129 ] ; 2015.
Abstract
Loss of protein quality control by the ubiquitin-proteasome system (UPS) during aging is one of the processes putatively contributing to cellular stress and Alzheimer's disease (AD) pathogenesis. Recently, pooled Genome Wide Association Studies (GWAS), pathway analysis and proteomics identified protein ubiquitination as one of the key modulators of AD. Mutations in ubiquitin B mRNA that result in UBB+1 dose-dependently cause an impaired UPS, subsequent accumulation of UBB+1 and most probably depositions of other aberrant proteins present in plaques and neurofibrillary tangles. We used specific immunohistochemical probes for a comprehensive topographic mapping of the UBB+1 distribution in the brains of transgenic mouse line 3413 overexpressing UBB+1. We also mapped the expression of UBB+1 in brain areas of AD patients selected based upon the distribution of UBB+1 in line 3413. Therefore, we focused on the olfactory bulb, basal ganglia, nucleus basalis of Meynert, inferior colliculus and raphe nuclei. UBB+1 distribution was compared with established probes for pre-tangles and tangles and Aβ plaques. UBB+1 distribution found in line 3413 is partly mirrored in the AD brain. Specifically, nuclei with substantial accumulations of tangle-bearing neurons, such as the nucleus basalis of Meynert and raphe nuclei also present high densities of UBB+1 positive tangles. Line 3413 is useful for studying the contribution of proteasomal dysfunction in AD. The findings are consistent with evidence that areas outside the forebrain are also affected in AD. Line 3413 may also be predictive for other conformational diseases, including related tauopathies and polyglutamine diseases, in which UBB+1 accumulates in their cellular hallmarks.
Url:
DOI: 10.3389/fnana.2015.00026
PubMed: 25852488
PubMed Central: 4362318
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<front><div type="abstract" xml:lang="en"><p>Loss of protein quality control by the ubiquitin-proteasome system (UPS) during aging is one of the processes putatively contributing to cellular stress and Alzheimer's disease (AD) pathogenesis. Recently, pooled Genome Wide Association Studies (GWAS), pathway analysis and proteomics identified protein ubiquitination as one of the key modulators of AD. Mutations in ubiquitin B mRNA that result in UBB<sup>+1</sup>
dose-dependently cause an impaired UPS, subsequent accumulation of UBB<sup>+1</sup>
and most probably depositions of other aberrant proteins present in plaques and neurofibrillary tangles. We used specific immunohistochemical probes for a comprehensive topographic mapping of the UBB<sup>+1</sup>
distribution in the brains of transgenic mouse line 3413 overexpressing UBB<sup>+1</sup>
. We also mapped the expression of UBB<sup>+1</sup>
in brain areas of AD patients selected based upon the distribution of UBB<sup>+1</sup>
in line 3413. Therefore, we focused on the olfactory bulb, basal ganglia, nucleus basalis of Meynert, inferior colliculus and raphe nuclei. UBB<sup>+1</sup>
distribution was compared with established probes for pre-tangles and tangles and Aβ plaques. UBB<sup>+1</sup>
distribution found in line 3413 is partly mirrored in the AD brain. Specifically, nuclei with substantial accumulations of tangle-bearing neurons, such as the nucleus basalis of Meynert and raphe nuclei also present high densities of UBB<sup>+1</sup>
positive tangles. Line 3413 is useful for studying the contribution of proteasomal dysfunction in AD. The findings are consistent with evidence that areas outside the forebrain are also affected in AD. Line 3413 may also be predictive for other conformational diseases, including related tauopathies and polyglutamine diseases, in which UBB<sup>+1</sup>
accumulates in their cellular hallmarks.</p>
</div>
</front>
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</author>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Front Neuroanat</journal-id>
<journal-id journal-id-type="iso-abbrev">Front Neuroanat</journal-id>
<journal-id journal-id-type="publisher-id">Front. Neuroanat.</journal-id>
<journal-title-group><journal-title>Frontiers in Neuroanatomy</journal-title>
</journal-title-group>
<issn pub-type="epub">1662-5129</issn>
<publisher><publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">25852488</article-id>
<article-id pub-id-type="pmc">4362318</article-id>
<article-id pub-id-type="doi">10.3389/fnana.2015.00026</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Neuroscience</subject>
<subj-group><subject>Original Research</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>Localization of mutant ubiquitin in the brain of a transgenic mouse line with proteasomal inhibition and its validation at specific sites in Alzheimer's disease</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Gentier</surname>
<given-names>Romina J. G.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<uri xlink:type="simple" xlink:href="http://community.frontiersin.org/people/u/193659"></uri>
</contrib>
<contrib contrib-type="author"><name><surname>Verheijen</surname>
<given-names>Bert M.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<uri xlink:type="simple" xlink:href="http://community.frontiersin.org/people/u/199221"></uri>
</contrib>
<contrib contrib-type="author"><name><surname>Zamboni</surname>
<given-names>Margherita</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<uri xlink:type="simple" xlink:href="http://community.frontiersin.org/people/u/195227"></uri>
</contrib>
<contrib contrib-type="author"><name><surname>Stroeken</surname>
<given-names>Maartje M. A.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hermes</surname>
<given-names>Denise J. H. P.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<uri xlink:type="simple" xlink:href="http://community.frontiersin.org/people/u/217228"></uri>
</contrib>
<contrib contrib-type="author"><name><surname>Küsters</surname>
<given-names>Benno</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
<uri xlink:type="simple" xlink:href="http://community.frontiersin.org/people/u/202347"></uri>
</contrib>
<contrib contrib-type="author"><name><surname>Steinbusch</surname>
<given-names>Harry W. M.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<uri xlink:type="simple" xlink:href="http://community.frontiersin.org/people/u/58470"></uri>
</contrib>
<contrib contrib-type="author"><name><surname>Hopkins</surname>
<given-names>David A.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff4"><sup>4</sup>
</xref>
<uri xlink:type="simple" xlink:href="http://community.frontiersin.org/people/u/201356"></uri>
</contrib>
<contrib contrib-type="author"><name><surname>Van Leeuwen</surname>
<given-names>Fred W.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="fn001"><sup>*</sup>
</xref>
<uri xlink:type="simple" xlink:href="http://community.frontiersin.org/people/u/44407"></uri>
</contrib>
</contrib-group>
<aff id="aff1"><sup>1</sup>
<institution>Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University</institution>
<country>Maastricht, Netherlands</country>
</aff>
<aff id="aff2"><sup>2</sup>
<institution>Department of Pathology, Radboud University Nijmegen Medical Center</institution>
<country>Nijmegen, Netherlands</country>
</aff>
<aff id="aff3"><sup>3</sup>
<institution>Department of Pathology, Maastricht University Medical Center</institution>
<country>Maastricht, Netherlands</country>
</aff>
<aff id="aff4"><sup>4</sup>
<institution>Department of Medical Neuroscience, Dalhousie University</institution>
<country>Halifax, NS, Canada</country>
</aff>
<author-notes><fn fn-type="edited-by"><p>Edited by: Ricardo Insausti, Universidad de Castilla-La Mancha, Spain</p>
</fn>
<fn fn-type="edited-by"><p>Reviewed by: Alino Martinez-Marcos, Universidad de Castilla-La Mancha, Spain; Gordon William Arbuthnott, Okinawa Institute of Science and Technology, Japan</p>
</fn>
<corresp id="fn001">*Correspondence: Fred W. Van Leeuwen, Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, Netherlands <email xlink:type="simple">f.vanleeuwen@maastrichtuniversity.nl</email>
</corresp>
</author-notes>
<pub-date pub-type="epub"><day>17</day>
<month>3</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="collection"><year>2015</year>
</pub-date>
<volume>9</volume>
<elocation-id>26</elocation-id>
<history><date date-type="received"><day>15</day>
<month>11</month>
<year>2014</year>
</date>
<date date-type="accepted"><day>21</day>
<month>2</month>
<year>2015</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2015 Gentier, Verheijen, Zamboni, Stroeken, Hermes, Küsters, Steinbusch, Hopkins and Van Leeuwen.</copyright-statement>
<copyright-year>2015</copyright-year>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</license-p>
</license>
</permissions>
<abstract><p>Loss of protein quality control by the ubiquitin-proteasome system (UPS) during aging is one of the processes putatively contributing to cellular stress and Alzheimer's disease (AD) pathogenesis. Recently, pooled Genome Wide Association Studies (GWAS), pathway analysis and proteomics identified protein ubiquitination as one of the key modulators of AD. Mutations in ubiquitin B mRNA that result in UBB<sup>+1</sup>
dose-dependently cause an impaired UPS, subsequent accumulation of UBB<sup>+1</sup>
and most probably depositions of other aberrant proteins present in plaques and neurofibrillary tangles. We used specific immunohistochemical probes for a comprehensive topographic mapping of the UBB<sup>+1</sup>
distribution in the brains of transgenic mouse line 3413 overexpressing UBB<sup>+1</sup>
. We also mapped the expression of UBB<sup>+1</sup>
in brain areas of AD patients selected based upon the distribution of UBB<sup>+1</sup>
in line 3413. Therefore, we focused on the olfactory bulb, basal ganglia, nucleus basalis of Meynert, inferior colliculus and raphe nuclei. UBB<sup>+1</sup>
distribution was compared with established probes for pre-tangles and tangles and Aβ plaques. UBB<sup>+1</sup>
distribution found in line 3413 is partly mirrored in the AD brain. Specifically, nuclei with substantial accumulations of tangle-bearing neurons, such as the nucleus basalis of Meynert and raphe nuclei also present high densities of UBB<sup>+1</sup>
positive tangles. Line 3413 is useful for studying the contribution of proteasomal dysfunction in AD. The findings are consistent with evidence that areas outside the forebrain are also affected in AD. Line 3413 may also be predictive for other conformational diseases, including related tauopathies and polyglutamine diseases, in which UBB<sup>+1</sup>
accumulates in their cellular hallmarks.</p>
</abstract>
<kwd-group><kwd>frameshift mutation</kwd>
<kwd>ubiquitin B<sup>+1</sup>
</kwd>
<kwd>olfactory bulb</kwd>
<kwd>basal ganglia</kwd>
<kwd>nucleus basalis of Meynert</kwd>
<kwd>inferior colliculus</kwd>
<kwd>raphe nuclei</kwd>
<kwd>RNA</kwd>
</kwd-group>
<counts><fig-count count="8"></fig-count>
<table-count count="6"></table-count>
<equation-count count="0"></equation-count>
<ref-count count="65"></ref-count>
<page-count count="21"></page-count>
<word-count count="14611"></word-count>
</counts>
</article-meta>
</front>
</pmc>
</record>
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