Rgs6 is Required for Adult Maintenance of Dopaminergic Neurons in the Ventral Substantia Nigra
Identifieur interne : 000149 ( Pmc/Curation ); précédent : 000148; suivant : 000150Rgs6 is Required for Adult Maintenance of Dopaminergic Neurons in the Ventral Substantia Nigra
Auteurs : Panojot Bifsha [Canada] ; Jianqi Yang [États-Unis] ; Rory A. Fisher [États-Unis] ; Jacques Drouin [Canada]Source :
- PLoS Genetics [ 1553-7390 ] ; 2014.
Abstract
Parkinson disease (PD) is characterized by the preferential, but poorly understood, vulnerability to degeneration of midbrain dopaminergic (mDA) neurons in the ventral substantia nigra compacta (vSNc). These sensitive mDA neurons express Pitx3, a transcription factor that is critical for their survival during development. We used this dependence to identify, by flow cytometry and expression profiling, the negative regulator of G-protein signaling Rgs6 for its restricted expression in these neurons. In contrast to
Url:
DOI: 10.1371/journal.pgen.1004863
PubMed: 25501001
PubMed Central: 4263397
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is Required for Adult Maintenance of Dopaminergic Neurons in the Ventral Substantia Nigra</title>
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is Required for Adult Maintenance of Dopaminergic Neurons in the Ventral Substantia Nigra</title>
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<series><title level="j">PLoS Genetics</title>
<idno type="ISSN">1553-7390</idno>
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<front><div type="abstract" xml:lang="en"><p>Parkinson disease (PD) is characterized by the preferential, but poorly understood, vulnerability to degeneration of midbrain dopaminergic (mDA) neurons in the ventral substantia nigra compacta (vSNc). These sensitive mDA neurons express Pitx3, a transcription factor that is critical for their survival during development. We used this dependence to identify, by flow cytometry and expression profiling, the negative regulator of G-protein signaling Rgs6 for its restricted expression in these neurons. In contrast to <italic>Pitx3<sup>−/−</sup>
</italic>
mDA neurons that die during fetal (vSNc) or post-natal (VTA) period, the vSNc mDA neurons of <italic>Rgs6</italic>
<sup>−/−</sup>
mutant mice begin to exhibit unilateral signs of degeneration at around 6 months of age, and by one year cell loss is observed in a fraction of mice. Unilateral cell loss is accompanied by contralateral degenerating neurons that exhibit smaller cell size, altered morphology and reduced dendritic network. The degenerating neurons have low levels of tyrosine hydroxylase (TH) and decreased nuclear Pitx3; accordingly, expression of many Pitx3 target gene products is altered, including Vmat2, Bdnf, Aldh1a1 (Adh2) and Fgf10. These low TH neurons also express markers of increased dopamine signaling, namely increased DAT and phospho-Erk1/2 expression. The late onset degeneration may reflect the protective action of Rgs6 against excessive DA signaling throughout life. Rgs6-dependent protection is thus critical for adult survival and maintenance of the vSNc mDA neurons that are most affected in PD.</p>
</div>
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</TEI>
<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Genet</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS Genet</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">plosgen</journal-id>
<journal-title-group><journal-title>PLoS Genetics</journal-title>
</journal-title-group>
<issn pub-type="ppub">1553-7390</issn>
<issn pub-type="epub">1553-7404</issn>
<publisher><publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">25501001</article-id>
<article-id pub-id-type="pmc">4263397</article-id>
<article-id pub-id-type="publisher-id">PGENETICS-D-14-02090</article-id>
<article-id pub-id-type="doi">10.1371/journal.pgen.1004863</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
<subj-group subj-group-type="Discipline-v2"><subject>Biology and Life Sciences</subject>
</subj-group>
<subj-group subj-group-type="Discipline-v2"><subject>Medicine and Health Sciences</subject>
</subj-group>
</article-categories>
<title-group><article-title><italic>Rgs6</italic>
is Required for Adult Maintenance of Dopaminergic Neurons in the Ventral Substantia Nigra</article-title>
<alt-title alt-title-type="running-head">Parkinson-Like Degeneration in <italic>Rgs6</italic>
Knockout Mice</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Bifsha</surname>
<given-names>Panojot</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Yang</surname>
<given-names>Jianqi</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Fisher</surname>
<given-names>Rory A.</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Drouin</surname>
<given-names>Jacques</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>*</sup>
</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>1</label>
<addr-line>Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM) Montréal, Quebec, Canada</addr-line>
</aff>
<aff id="aff2"><label>2</label>
<addr-line>Division of Experimental Medicine, McGill University, Montréal, Quebec, Canada</addr-line>
</aff>
<aff id="aff3"><label>3</label>
<addr-line>Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Copenhaver</surname>
<given-names>Gregory P.</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1"><addr-line>The University of North Carolina at Chapel Hill, United States of America</addr-line>
</aff>
<author-notes><corresp id="cor1">* E-mail: <email>jacques.drouin@ircm.qc.ca</email>
</corresp>
<fn fn-type="conflict"><p>The authors have declared that no competing interests exist.</p>
</fn>
<fn fn-type="con"><p>Conceived and designed the experiments: PB JY RAF JD. Performed the experiments: PB JY. Analyzed the data: PB JY RAF JD. Contributed reagents/materials/analysis tools: PB JY RAF JD. Wrote the paper: PB JY RAF JD.</p>
</fn>
</author-notes>
<pub-date pub-type="collection"><month>12</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="epub"><day>11</day>
<month>12</month>
<year>2014</year>
</pub-date>
<volume>10</volume>
<issue>12</issue>
<elocation-id>e1004863</elocation-id>
<history><date date-type="received"><day>31</day>
<month>7</month>
<year>2014</year>
</date>
<date date-type="accepted"><day>29</day>
<month>10</month>
<year>2014</year>
</date>
</history>
<permissions><copyright-statement>© 2014 Bifsha et al</copyright-statement>
<copyright-year>2014</copyright-year>
<copyright-holder>Bifsha et al</copyright-holder>
<license 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, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.</license-p>
</license>
</permissions>
<abstract><p>Parkinson disease (PD) is characterized by the preferential, but poorly understood, vulnerability to degeneration of midbrain dopaminergic (mDA) neurons in the ventral substantia nigra compacta (vSNc). These sensitive mDA neurons express Pitx3, a transcription factor that is critical for their survival during development. We used this dependence to identify, by flow cytometry and expression profiling, the negative regulator of G-protein signaling Rgs6 for its restricted expression in these neurons. In contrast to <italic>Pitx3<sup>−/−</sup>
</italic>
mDA neurons that die during fetal (vSNc) or post-natal (VTA) period, the vSNc mDA neurons of <italic>Rgs6</italic>
<sup>−/−</sup>
mutant mice begin to exhibit unilateral signs of degeneration at around 6 months of age, and by one year cell loss is observed in a fraction of mice. Unilateral cell loss is accompanied by contralateral degenerating neurons that exhibit smaller cell size, altered morphology and reduced dendritic network. The degenerating neurons have low levels of tyrosine hydroxylase (TH) and decreased nuclear Pitx3; accordingly, expression of many Pitx3 target gene products is altered, including Vmat2, Bdnf, Aldh1a1 (Adh2) and Fgf10. These low TH neurons also express markers of increased dopamine signaling, namely increased DAT and phospho-Erk1/2 expression. The late onset degeneration may reflect the protective action of Rgs6 against excessive DA signaling throughout life. Rgs6-dependent protection is thus critical for adult survival and maintenance of the vSNc mDA neurons that are most affected in PD.</p>
</abstract>
<abstract abstract-type="summary"><title>Author Summary</title>
<p>The locomotor deficits associated with Parkinson disease result from the death of a specific subset of dopamine neurons in the ventral part of the midbrain. The reason for the greater sensitivity to degeneration of those, relative to other, neurons is not clear. Prior work showed that the Pitx3 transcription factor is specifically expressed in these neurons where it has a survival role during development. The present work identified a cell signaling component, Rgs6, that is also restricted to the sensitive neurons in the midbrain and that exerts a protective function, particularly late in life. While the loss of Rgs6 function may predispose or contribute to Parkinson disease, its stimulation may provide a novel therapeutic avenue to treat Parkinson disease.</p>
</abstract>
<funding-group><funding-statement>Funding for this project was provided by NIH CA161882 to RAF and by the Parkinson Society of Canada and Canadian Institutes of Health Research MOP-123213 to JD and FRSQ scholarship to PB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement>
</funding-group>
<counts><page-count count="12"></page-count>
</counts>
<custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name>
<meta-value>The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
<notes><title>Data Availability</title>
<p>The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.</p>
</notes>
</front>
</pmc>
</record>
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