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Widespread Nitration of Pathological Inclusions in Neurodegenerative Synucleinopathies

Identifieur interne : 003186 ( Main/Corpus ); précédent : 003185; suivant : 003187

Widespread Nitration of Pathological Inclusions in Neurodegenerative Synucleinopathies

Auteurs : John E. Duda ; Benoit I. Giasson ; Qiping Chen ; Tamar L. Gur ; Howard I. Hurtig ; Matthew B. Stern ; Steven M. Gollomp ; Harry Ischiropoulos ; Virginia M.-Y. Lee ; John Q. Trojanowski

Source :

The American Journal of Pathology [ 0002-9440 ] ; 2000.

RBID : ISTEX:9DCA7685D30C7D05A92A3C635DCF14ACC1A7D7F5

Abstract

Reactive nitrogen species may play a mechanistic role in neurodegenerative diseases by posttranslationally altering normal brain proteins. In support of this hypothesis, we demonstrate that an anti-3-nitrotyrosine polyclonal antibody stains all of the major hallmark lesions of synucleinopathies including Lewy bodies, Lewy neurites and neuraxonal spheroids in dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, and neurodegeneration with brain iron accumulation type 1, as well as glial and neuronal cytoplasmic inclusions in multiple system atrophy. This antibody predominantly recognized nitrated -synuclein when compared to other in vitro nitrated constituents of these pathological lesions, such as neurofilament subunits and microtubules. Collectively, these findings imply that -synuclein is nitrated in pathological lesions. The widespread presence of nitrated -synuclein in diverse intracellular inclusions suggests that oxidation/nitration is involved in the onset and/or progression of neurodegenerative diseases.

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https://api.istex.fr/document/9DCA7685D30C7D05A92A3C635DCF14ACC1A7D7F5/fulltext/pdf

DOI: 10.1016/S0002-9440(10)64781-5

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<front><div type="abstract">Reactive nitrogen species may play a mechanistic role in neurodegenerative diseases by posttranslationally altering normal brain proteins. In support of this hypothesis, we demonstrate that an anti-3-nitrotyrosine polyclonal antibody stains all of the major hallmark lesions of synucleinopathies including Lewy bodies, Lewy neurites and neuraxonal spheroids in dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, and neurodegeneration with brain iron accumulation type 1, as well as glial and neuronal cytoplasmic inclusions in multiple system atrophy. This antibody predominantly recognized nitrated -synuclein when compared to other in vitro nitrated constituents of these pathological lesions, such as neurofilament subunits and microtubules. Collectively, these findings imply that -synuclein is nitrated in pathological lesions. The widespread presence of nitrated -synuclein in diverse intracellular inclusions suggests that oxidation/nitration is involved in the onset and/or progression of neurodegenerative diseases.</div>
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<notesStmt><note>Supported by grants from the National Institutes of Health and by a Pioneer Award from the Alzheimer's Association. B. I. G. is the recipient of a fellowship from the Human Frontier Science Program Organization.</note>
<note type="content">Section title: Short Communications</note>
<note type="content">Figure 1: Immunostaining with the 3-NT pAb in sections of DLB, LBVAD, MSA, and NBIA1 brains. a and b: 3-NT immunostaining of -syn lesions in the cingulate cortex of DLB and LBVAD brains, respectively. The insert in a shows a high-power magnification of a typical 3-NT-positive LB and LN from the same section. c: Intense 3-NT immunostaining throughout a classical LB in a pigmented substantia nigra pars compacta neuron of an LBVAD brain. df: Robust 3-NT immunostaining is seen in multiple GCIs throughout cerebellar white matter of three different MSA brains. In the NBIA1 brain, intense 3-NT immunoreactivity is seen in LB-like inclusions of the globus pallidus (g and h), as well as in neuraxonal spheroids (i), and GCIs from the insular cortex (j). Scale bars, 30 m (a, b, df)and 10 m (inset in a, c, gj).</note>
<note type="content">Figure 2: Western blot analysis of 3-NT pAb antibody. A: Coomassie-stained gel of in vitro nitrated -syn, tubulin, NFL, NFM, and NFH. Five g of each protein were resolved by electrophoresis on separate lanes of a discontinuous 6 to 10 to 12 sodium dodecyl sulfate-polyacrylamide gel. The arrow on the left denotes monomeric -syn. B: In Western blots the 3-NT pAb variably recognizes each of the nitrated proteins but none are as intensely immunoreactive as nitrated -syn. Note the robust recognition of monomeric -syn as well as higher oligomeric -syn species by this antibody. The arrows in B identify the far less intensely labeled immunobands for each of the other proteins. Fifty ng of each protein were resolved by electrophoresis on a discontinuous 6 to 10 to 12 sodium dodecyl sulfate-polyacrylamide gel. After electrophoretic transfer to nitrocellulose membrane, the blot was blocked with 5 skimmed milk, sequentially incubated with the 3-NT pAb and anti-rabbit-horseradish peroxidase-conjugated antibody and developed with enhanced luminol reagents (Dupont-New England Nuclear). The position of the molecular weight markers are indicated on the left.</note>
<note type="content">Table 1: Case Demographics</note>
<note type="content">Table 2: Percentage of 3-NT-Positive Inclusions</note>
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<abstract><p>Reactive nitrogen species may play a mechanistic role in neurodegenerative diseases by posttranslationally altering normal brain proteins. In support of this hypothesis, we demonstrate that an anti-3-nitrotyrosine polyclonal antibody stains all of the major hallmark lesions of synucleinopathies including Lewy bodies, Lewy neurites and neuraxonal spheroids in dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, and neurodegeneration with brain iron accumulation type 1, as well as glial and neuronal cytoplasmic inclusions in multiple system atrophy. This antibody predominantly recognized nitrated -synuclein when compared to other in vitro nitrated constituents of these pathological lesions, such as neurofilament subunits and microtubules. Collectively, these findings imply that -synuclein is nitrated in pathological lesions. The widespread presence of nitrated -synuclein in diverse intracellular inclusions suggests that oxidation/nitration is involved in the onset and/or progression of neurodegenerative diseases.</p>
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 <ce:floats> <ce:figure id="fig1"> <ce:label>Figure 1</ce:label>
 <ce:caption> <ce:simple-para id="spara10">Immunostaining with the 3-NT pAb in sections of DLB, LBVAD, MSA, and NBIA1 brains. <ce:bold>a</ce:bold>
 and <ce:bold>b:</ce:bold>
 3-NT immunostaining of α-syn lesions in the cingulate cortex of DLB and LBVAD brains, respectively. The <ce:bold>insert</ce:bold>
 in <ce:bold>a</ce:bold>
 shows a high-power magnification of a typical 3-NT-positive LB and LN from the same section. <ce:bold>c:</ce:bold>
 Intense 3-NT immunostaining throughout a classical LB in a pigmented substantia nigra pars compacta neuron of an LBVAD brain. <ce:bold>d–f:</ce:bold>
 Robust 3-NT immunostaining is seen in multiple GCIs throughout cerebellar white matter of three different MSA brains. In the NBIA1 brain, intense 3-NT immunoreactivity is seen in LB-like inclusions of the globus pallidus (<ce:bold>g</ce:bold>
 and <ce:bold>h</ce:bold>
), as well as in neuraxonal spheroids (<ce:bold>i</ce:bold>
), and GCIs from the insular cortex (<ce:bold>j</ce:bold>
). Scale bars, 30 μm (<ce:bold>a, b, d–f</ce:bold>
)and 10 μm (<ce:bold>inset</ce:bold>
 in <ce:bold>a, c, g–j</ce:bold>
).</ce:simple-para>
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 <ce:figure id="fig2"> <ce:label>Figure 2</ce:label>
 <ce:caption> <ce:simple-para id="spara20">Western blot analysis of 3-NT pAb antibody. <ce:bold>A:</ce:bold>
 Coomassie-stained gel of <ce:italic>in vitro</ce:italic>
 nitrated α-syn, tubulin, NFL, NFM, and NFH. Five μg of each protein were resolved by electrophoresis on separate lanes of a discontinuous 6% to 10% to 12% sodium dodecyl sulfate-polyacrylamide gel. The <ce:bold>arrow</ce:bold>
 on the <ce:bold>left</ce:bold>
 denotes monomeric α-syn. <ce:bold>B:</ce:bold>
 In Western blots the 3-NT pAb variably recognizes each of the nitrated proteins but none are as intensely immunoreactive as nitrated α-syn. Note the robust recognition of monomeric α-syn as well as higher oligomeric α-syn species by this antibody. The <ce:bold>arrows</ce:bold>
 in <ce:bold>B</ce:bold>
 identify the far less intensely labeled immunobands for each of the other proteins. Fifty ng of each protein were resolved by electrophoresis on a discontinuous 6% to 10% to 12% sodium dodecyl sulfate-polyacrylamide gel. After electrophoretic transfer to nitrocellulose membrane, the blot was blocked with 5% skimmed milk, sequentially incubated with the 3-NT pAb and anti-rabbit-horseradish peroxidase-conjugated antibody and developed with enhanced luminol reagents (Dupont-New England Nuclear). The position of the molecular weight markers are indicated on the <ce:bold>left</ce:bold>
.</ce:simple-para>
 </ce:caption>
 <ce:link locator="gr2"></ce:link>
 </ce:figure>
 <ce:table id="tbl1" frame="topbot" rowsep="0" colsep="0"> <ce:label>Table 1</ce:label>
 <ce:caption> <ce:simple-para id="spara30">Case Demographics</ce:simple-para>
 </ce:caption>
 <tgroup cols="5" altimg="si1.gif"> <colspec colnum="1" colname="col1"></colspec>
 <colspec colnum="2" colname="col2"></colspec>
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 <thead> <row valign="top" rowsep="1"> <entry align="left">Case no.</entry>
 <entry align="center">Age</entry>
 <entry align="center">Sex</entry>
 <entry align="center">Postmortem interval</entry>
 <entry align="center">Diagnosis</entry>
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 </thead>
 <tbody> <row valign="top"> <entry align="left">1</entry>
 <entry align="char" char=".">55</entry>
 <entry align="left">M</entry>
 <entry align="char" char=".">7</entry>
 <entry align="left">MSA</entry>
 </row>
 <row valign="top"> <entry align="left">2</entry>
 <entry align="char" char=".">67</entry>
 <entry align="left">F</entry>
 <entry align="char" char=".">5</entry>
 <entry align="left">MSA</entry>
 </row>
 <row valign="top"> <entry align="left">3</entry>
 <entry align="char" char=".">60</entry>
 <entry align="left">F</entry>
 <entry align="char" char=".">10.5</entry>
 <entry align="left">MSA</entry>
 </row>
 <row valign="top"> <entry align="left">4</entry>
 <entry align="char" char=".">64</entry>
 <entry align="left">F</entry>
 <entry align="char" char=".">17</entry>
 <entry align="left">MSA</entry>
 </row>
 <row valign="top"> <entry align="left">5</entry>
 <entry align="char" char=".">72</entry>
 <entry align="left">F</entry>
 <entry align="char" char=".">14</entry>
 <entry align="left">MSA</entry>
 </row>
 <row valign="top"> <entry align="left">6</entry>
 <entry align="char" char=".">43</entry>
 <entry align="left">M</entry>
 <entry align="char" char=".">16.5</entry>
 <entry align="left">MSA</entry>
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 <row valign="top"> <entry align="left">7</entry>
 <entry align="char" char=".">79</entry>
 <entry align="left">M</entry>
 <entry align="char" char=".">16</entry>
 <entry align="left">MSA</entry>
 </row>
 <row valign="top"> <entry align="left">8</entry>
 <entry align="char" char=".">58</entry>
 <entry align="left">M</entry>
 <entry align="char" char=".">20.5</entry>
 <entry align="left">DLB</entry>
 </row>
 <row valign="top"> <entry align="left">9</entry>
 <entry align="char" char=".">83</entry>
 <entry align="left">F</entry>
 <entry align="char" char=".">14.5</entry>
 <entry align="left">DLB</entry>
 </row>
 <row valign="top"> <entry align="left">10</entry>
 <entry align="char" char=".">76</entry>
 <entry align="left">M</entry>
 <entry align="char" char=".">13.5</entry>
 <entry align="left">DLB</entry>
 </row>
 <row valign="top"> <entry align="left">11</entry>
 <entry align="char" char=".">74</entry>
 <entry align="left">M</entry>
 <entry align="char" char=".">15.5</entry>
 <entry align="left">DLB</entry>
 </row>
 <row valign="top"> <entry align="left">13</entry>
 <entry align="char" char=".">63</entry>
 <entry align="left">F</entry>
 <entry align="char" char=".">22</entry>
 <entry align="left">DLB</entry>
 </row>
 <row valign="top"> <entry align="left">14</entry>
 <entry align="char" char=".">79</entry>
 <entry align="left">M</entry>
 <entry align="char" char=".">12</entry>
 <entry align="left">DLB</entry>
 </row>
 <row valign="top"> <entry align="left">12</entry>
 <entry align="char" char=".">65</entry>
 <entry align="left">M</entry>
 <entry align="char" char=".">9.5</entry>
 <entry align="left">LBVAD</entry>
 </row>
 <row valign="top"> <entry align="left">15</entry>
 <entry align="char" char=".">73</entry>
 <entry align="left">M</entry>
 <entry align="char" char=".">12</entry>
 <entry align="left">LBVAD</entry>
 </row>
 <row valign="top"> <entry align="left">16</entry>
 <entry align="char" char=".">79</entry>
 <entry align="left">M</entry>
 <entry align="char" char=".">20.5</entry>
 <entry align="left">LBVAD</entry>
 </row>
 <row valign="top"> <entry align="left">17</entry>
 <entry align="char" char=".">82</entry>
 <entry align="left">F</entry>
 <entry align="char" char=".">8</entry>
 <entry align="left">LBVAD</entry>
 </row>
 <row valign="top"> <entry align="left">18</entry>
 <entry align="char" char=".">77</entry>
 <entry align="left">M</entry>
 <entry align="char" char=".">10.5</entry>
 <entry align="left">LBVAD</entry>
 </row>
 <row valign="top"> <entry align="left">19</entry>
 <entry align="char" char=".">29</entry>
 <entry align="left">M</entry>
 <entry align="char" char=".">6</entry>
 <entry align="left">NBIA1</entry>
 </row>
 </tbody>
 </tgroup>
 </ce:table>
 <ce:table id="tbl2" frame="topbot" rowsep="0" colsep="0"> <ce:label>Table 2</ce:label>
 <ce:caption> <ce:simple-para id="spara40">Percentage of 3-NT-Positive Inclusions</ce:simple-para>
 </ce:caption>
 <tgroup cols="3" altimg="si2.gif"> <colspec colnum="1" colname="col1"></colspec>
 <colspec colnum="2" colname="col2"></colspec>
 <colspec colnum="3" colname="col3"></colspec>
 <thead> <row valign="top" rowsep="1"> <entry align="left">Case no.</entry>
 <entry align="center">Diagnosis</entry>
 <entry align="center">Percentage</entry>
 </row>
 </thead>
 <tbody> <row valign="top"> <entry align="left">1</entry>
 <entry align="left">MSA</entry>
 <entry align="char" char=".">76</entry>
 </row>
 <row valign="top"> <entry align="left">2</entry>
 <entry align="left">MSA</entry>
 <entry align="char" char=".">57</entry>
 </row>
 <row valign="top"> <entry align="left">3</entry>
 <entry align="left">MSA</entry>
 <entry align="char" char=".">60</entry>
 </row>
 <row valign="top"> <entry align="left">4</entry>
 <entry align="left">MSA</entry>
 <entry align="char" char=".">56</entry>
 </row>
 <row valign="top"> <entry align="left">5</entry>
 <entry align="left">MSA</entry>
 <entry align="char" char=".">63</entry>
 </row>
 <row valign="top"> <entry align="left">6</entry>
 <entry align="left">MSA</entry>
 <entry align="char" char=".">70</entry>
 </row>
 <row valign="top"> <entry align="left">7</entry>
 <entry align="left">MSA</entry>
 <entry align="char" char=".">76</entry>
 </row>
 <row valign="top"> <entry align="left">8</entry>
 <entry align="left">DLB</entry>
 <entry align="char" char=".">63</entry>
 </row>
 <row valign="top"> <entry align="left">9</entry>
 <entry align="left">DLB</entry>
 <entry align="char" char=".">61</entry>
 </row>
 <row valign="top"> <entry align="left">10</entry>
 <entry align="left">DLB</entry>
 <entry align="center">NA</entry>
 </row>
 <row valign="top"> <entry align="left">11</entry>
 <entry align="left">DLB</entry>
 <entry align="char" char=".">100*</entry>
 </row>
 <row valign="top"> <entry align="left">12</entry>
 <entry align="left">DLB</entry>
 <entry align="char" char=".">90</entry>
 </row>
 <row valign="top"> <entry align="left">13</entry>
 <entry align="left">DLB</entry>
 <entry align="char" char=".">67</entry>
 </row>
 <row valign="top"> <entry align="left">14</entry>
 <entry align="left">LBVAD</entry>
 <entry align="char" char=".">79</entry>
 </row>
 <row valign="top"> <entry align="left">15</entry>
 <entry align="left">LBVAD</entry>
 <entry align="char" char=".">60</entry>
 </row>
 <row valign="top"> <entry align="left">16</entry>
 <entry align="left">LBVAD</entry>
 <entry align="char" char=".">57</entry>
 </row>
 <row valign="top"> <entry align="left">17</entry>
 <entry align="left">LBVAD</entry>
 <entry align="char" char=".">80</entry>
 </row>
 <row valign="top"> <entry align="left">18</entry>
 <entry align="left">LBVAD</entry>
 <entry align="char" char=".">63</entry>
 </row>
 </tbody>
 </tgroup>
 <ce:legend> <ce:simple-para id="spara50">Asterisk indicates a DLB brain that had slightly more 3-NT-immunolabeled LBs than those labeled by antibodies to α-syn in adjacent sections.</ce:simple-para>
 </ce:legend>
 </ce:table>
 </ce:floats>
 <head> <ce:article-footnote> <ce:note-para>Supported by grants from the National Institutes of Health and by a Pioneer Award from the Alzheimer's Association. B. I. G. is the recipient of a fellowship from the Human Frontier Science Program Organization.</ce:note-para>
 </ce:article-footnote>
 <ce:dochead> <ce:textfn>Short Communications</ce:textfn>
 </ce:dochead>
 <ce:title>Widespread Nitration of Pathological Inclusions in Neurodegenerative Synucleinopathies</ce:title>
 <ce:author-group> <ce:author> <ce:given-name>John E.</ce:given-name>
 <ce:surname>Duda</ce:surname>
<ce:cross-ref refid="aff1"><ce:sup>*</ce:sup>
</ce:cross-ref>
 </ce:author>
 <ce:author> <ce:given-name>Benoit I.</ce:given-name>
 <ce:surname>Giasson</ce:surname>
<ce:cross-ref refid="aff1"><ce:sup>*</ce:sup>
</ce:cross-ref>
 </ce:author>
 <ce:author> <ce:given-name>Qiping</ce:given-name>
 <ce:surname>Chen</ce:surname>
<ce:cross-ref refid="aff2"><ce:sup>†</ce:sup>
</ce:cross-ref>
 </ce:author>
 <ce:author> <ce:given-name>Tamar L.</ce:given-name>
 <ce:surname>Gur</ce:surname>
<ce:cross-ref refid="aff1"><ce:sup>*</ce:sup>
</ce:cross-ref>
 </ce:author>
 <ce:author> <ce:given-name>Howard I.</ce:given-name>
 <ce:surname>Hurtig</ce:surname>
<ce:cross-ref refid="aff3"><ce:sup>‡</ce:sup>
</ce:cross-ref>
 </ce:author>
 <ce:author> <ce:given-name>Matthew B.</ce:given-name>
 <ce:surname>Stern</ce:surname>
<ce:cross-ref refid="aff3"><ce:sup>‡</ce:sup>
</ce:cross-ref>
 </ce:author>
 <ce:author> <ce:given-name>Steven M.</ce:given-name>
 <ce:surname>Gollomp</ce:surname>
<ce:cross-ref refid="aff3"><ce:sup>‡</ce:sup>
</ce:cross-ref>
 </ce:author>
 <ce:author> <ce:given-name>Harry</ce:given-name>
 <ce:surname>Ischiropoulos</ce:surname>
<ce:cross-ref refid="aff2"><ce:sup>†</ce:sup>
</ce:cross-ref>
 </ce:author>
 <ce:author> <ce:given-name>Virginia M.-Y.</ce:given-name>
 <ce:surname>Lee</ce:surname>
<ce:cross-ref refid="aff1"><ce:sup>*</ce:sup>
</ce:cross-ref>
 </ce:author>
 <ce:author> <ce:given-name>John Q.</ce:given-name>
 <ce:surname>Trojanowski</ce:surname>
<ce:cross-ref refid="aff1"><ce:sup>*</ce:sup>
</ce:cross-ref>
<ce:cross-ref refid="cor1"><ce:sup>*</ce:sup>
</ce:cross-ref>
 <ce:e-address type="email">trojanow@mail.med.upenn.edu</ce:e-address>
 </ce:author>
 <ce:affiliation id="aff1"> <ce:label>*</ce:label>
 <ce:textfn>From the Center for Neurodegenerative Disease Research and Department of Pathology and Laboratory Medicine, The University of Pennsylvania, Philadelphia</ce:textfn>
 </ce:affiliation>
 <ce:affiliation id="aff3"> <ce:label>‡</ce:label>
 <ce:textfn>Department of Neurology, The University of Pennsylvania, Philadelphia</ce:textfn>
 </ce:affiliation>
 <ce:affiliation id="aff2"> <ce:label>†</ce:label>
 <ce:textfn>Stokes Research Institute and Department of Biochemistry and Biophysics, Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, Pennsylvania</ce:textfn>
 </ce:affiliation>
 <ce:correspondence id="cor1"> <ce:label>*</ce:label>
 <ce:text>Address reprint requests to John Q. Trojanowski, MD, PhD, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 3rd Floor Maloney Building, 3600 Spruce St., Philadelphia, PA 19104. E-mail:</ce:text>
 </ce:correspondence>
 </ce:author-group>
 <ce:date-accepted day="3" month="8" year="2000"></ce:date-accepted>
 <ce:abstract> <ce:abstract-sec> <ce:simple-para id="spara60">Reactive nitrogen species may play a mechanistic role in neurodegenerative diseases by posttranslationally altering normal brain proteins. In support of this hypothesis, we demonstrate that an anti-3-nitrotyrosine polyclonal antibody stains all of the major hallmark lesions of synucleinopathies including Lewy bodies, Lewy neurites and neuraxonal spheroids in dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, and neurodegeneration with brain iron accumulation type 1, as well as glial and neuronal cytoplasmic inclusions in multiple system atrophy. This antibody predominantly recognized nitrated α-synuclein when compared to other <ce:italic>in vitro</ce:italic>
 nitrated constituents of these pathological lesions, such as neurofilament subunits and microtubules. Collectively, these findings imply that α-synuclein is nitrated in pathological lesions. The widespread presence of nitrated α-synuclein in diverse intracellular inclusions suggests that oxidation/nitration is involved in the onset and/or progression of neurodegenerative diseases.</ce:simple-para>
 </ce:abstract-sec>
 </ce:abstract>
 </head>
 <body> <ce:sections> <ce:para id="para10">Oxidative injury has been implicated in the pathogenesis of numerous neurodegenerative diseases including Alzheimer's disease,<ce:cross-ref refid="bib1"><ce:sup>1</ce:sup>
</ce:cross-ref>
 Parkinson's disease,<ce:cross-refs refid="bib2 bib3"><ce:sup>2,3</ce:sup>
</ce:cross-refs>
 dementia with Lewy bodies (DLB),<ce:cross-ref refid="bib4"><ce:sup>4</ce:sup>
</ce:cross-ref>
 amyotrophic lateral sclerosis,<ce:cross-ref refid="bib5"><ce:sup>5</ce:sup>
</ce:cross-ref>
 and Huntington's disease.<ce:cross-ref refid="bib6"><ce:sup>6</ce:sup>
</ce:cross-ref>
 Oxidative injury occurs when an imbalance is created by the production of reactive species that escape or overwhelm the compensatory anti-oxidant capacity of a cell. Both reactive oxygen and nitrogen species are produced <ce:italic>in vivo</ce:italic>
 and may act synergistically to form nitrating agents that can modify proteins as well as lipids and thiol and aldehyde moieties in other biomolecules.<ce:cross-refs refid="bib7 bib8"><ce:sup>7,8</ce:sup>
</ce:cross-refs>
 More specifically, tyrosine residues or free tyrosine can be modified by peroxynitrite, a compound generated by the reaction of superoxide radical and nitric oxide, to generate 3-nitrotyrosine (3-NT). The formation of the peroxynitrite-CO<ce:inf>2</ce:inf>
 adduct or the presence of other catalysts (redox active metal, metalloproteins. increases the reactivity of peroxynitrite.<ce:cross-refs refid="bib9 bib10"><ce:sup>9,10</ce:sup>
</ce:cross-refs>
 Further, in the presence of myeloperoxidase or eosinophil peroxidase, hydrogen peroxide can oxidize nitrite to another biologically active nitrating agent,<ce:cross-refs refid="bib11 bib12"><ce:sup>11,12</ce:sup>
</ce:cross-refs>
 which also generates 3-NT. Nitrated tyrosine residues have been detected in Lewy bodies (LBs) of Parkinson's disease brains<ce:cross-ref refid="bib13"><ce:sup>13</ce:sup>
</ce:cross-ref>
 and in neurofibrillary tangles of Alzheimer's disease brains,<ce:cross-refs refid="bib14 bib15"><ce:sup>14,15</ce:sup>
</ce:cross-refs>
 but no studies have examined these or additional hallmark lesions of other neurodegenerative disorders and the molecular target(s) of nitration in these lesions have yet to be identified.</ce:para>
 <ce:para id="para20">α-Synuclein (α-syn) is a 140-amino acid long highly conserved protein that is abundant in neurons, particularly in presynaptic terminals.<ce:cross-refs refid="bib16 bib17"><ce:sup>16,17</ce:sup>
</ce:cross-refs>
 Two mutations in the α-syn gene have been shown to be pathogenic for familial Parkinson's disease in rare kindreds,<ce:cross-refs refid="bib18 bib19 bib20"><ce:sup>18–20</ce:sup>
</ce:cross-refs>
 and it has been demonstrated that α-syn is the major component of LBs and Lewy neurites (LNs) in Parkinson's disease, DLB, and the LB variant of Alzheimer's disease (LBVAD).<ce:cross-refs refid="bib21 bib22 bib23 bib24 bib25 bib26 bib27"><ce:sup>21–27</ce:sup>
</ce:cross-refs>
 More recently, α-syn has been recognized to be a major component of the glial (GCIs) and neuronal cytoplasmic inclusions in multiple system atrophy (MSA. brains<ce:cross-refs refid="bib28 bib29 bib30 bib31 bib32 bib33 bib34"><ce:sup>28–34</ce:sup>
</ce:cross-refs>
 as well as of the LB-like inclusions, neuraxonal spheroids, and LNs in neurodegeneration with brain iron accumulation type 1 (NBIA1; previously known as Hallervorden-Spatz disease).<ce:cross-refs refid="bib33 bib35 bib36"><ce:sup>33,35,36</ce:sup>
</ce:cross-refs>
 Thus, neurodegenerative disorders characterized neuropathologically by α-syn lesions now are referred to as synucleinopathies.</ce:para>
 <ce:para id="para30">Here, we report that the majority of α-syn inclusions in DLB, LBVAD, MSA, and NBIA1 contain nitrated proteins. Further, we also demonstrate that α-syn, nitrated <ce:italic>in vitro</ce:italic>
, is recognized by the rabbit anti-3-NT polyclonal antibody (3-NT pAb) in Western blots thereby implicating α-syn as a plausible target for nitrative modification in these inclusions. Thus, we infer from these data that oxidative/nitrative modifications of α-syn are involved in mechanisms underlying neurodegenerative synucleinopathies.</ce:para>
 <ce:section id="cesec10"> <ce:section-title>Materials and Methods</ce:section-title>
 <ce:section id="cesec20"> <ce:section-title><ce:italic>In Vitro</ce:italic>
 Nitration and Western Blot Analysis</ce:section-title>
 <ce:para id="para40">To assess the relative specificity of the 3-NT pAb for proteins previously detected in synucleinopathy lesions, we performed Western blot analyses with this antibody on purified proteins after <ce:italic>in vitro</ce:italic>
 nitration. Recombinant human α-syn was expressed and purified from bacteria as previously described.<ce:cross-ref refid="bib37"><ce:sup>37</ce:sup>
</ce:cross-ref>
 Recombinant mouse low molecular weight neurofilament (NF) protein (NFL. were expressed in <ce:italic>Escherichia coli</ce:italic>
 BL21 (DE3) using a mouse NFL cDNA cloned into the pET-23d expression vector (Novagen, Inc. Madison, WI) after which transformed bacteria were selected and maintained in Luria-Bertani medium (10 g/ml bacto-tryptone, 5 g/ml bacto-yeast extract, 10 g/ml NaCl) or Terrific Broth (12 g/ml bacto-tryptone, 24 g/ml bacto-yeast extract, 0.4% gycerol, 17 mmol/L KH<ce:inf>2</ce:inf>
PO<ce:inf>4</ce:inf>
, 72 mmol/L K<ce:inf>2</ce:inf>
PO<ce:inf>4</ce:inf>
) containing 100 μg/ml ampicillin. Bacteria were grown to an OD<ce:inf>600</ce:inf>
 of 0.6 and the expression of the recombinant protein was induced with 0.5 mmol/L of isopropyl-β-<ce:small-caps>d</ce:small-caps>
-thiogalactopyranoside for 2 hours. To recover bacterially expressed NFL, cells were pelleted, resuspended into lysis buffer (25% sucrose, 1 mmol/L ethylenediaminetetraacetic acid, 50 mmol/L Tris, pH 8.0, 2 mg/ml lysozyme, and a cocktail of protease inhibitors) and incubated on ice for 30 minutes. Ten mmol/L of MgCl<ce:inf>2</ce:inf>
, 1 mmol/L MnCl<ce:inf>2</ce:inf>
, 10 μg/ml DNase 1 and 10 μg/ml RNase A were added to the homogenate, which was incubated on ice for another 30 minutes. Two ml of detergent buffer (0.2 mol/L NaCl, 1% deoxycholic acid, 1% Nonidet P-40, 20 mmol/L Tris, pH 7.5, 2 mmol/L ethylenediaminetetraacetic acid) per ml of lysis buffer were added and, after vigorous mixing, the insoluble material was sedimented at 5,000 × <ce:italic>g</ce:italic>
 for 30 minutes. The supernatant was discarded and the pellet was repeatedly washed with buffer containing 0.5% Triton and 1 mmol/L ethylenediaminetetraacetic acid to generate a highly compact pellet which was resuspended in 8 mol/L urea, 1% β-mercaptoethanol, 10 mmol/L NaPO<ce:inf>4</ce:inf>
, pH 7.0, for subsequent purification of NFL using hydroxylapatite (Bio-Rad Laboratories, Richmond, CA).<ce:cross-ref refid="bib38"><ce:sup>38</ce:sup>
</ce:cross-ref>
 Medium (NFM) and high (NFH. molecular weight NF proteins were purified from bovine spinal cords as previously described.<ce:cross-ref refid="bib39"><ce:sup>39</ce:sup>
</ce:cross-ref>
 Tubulin proteins recovered from phosphocellulose purified bovine microtubules were purchased from Cytoskeleton, Inc., Denver, CO. All of these proteins were nitrated with a 10-fold molar excess of peroxynitrite as previously described,<ce:cross-ref refid="bib40"><ce:sup>40</ce:sup>
</ce:cross-ref>
 and then the relative specificity of the 3-NT pAb for each of these proteins was assessed by Western blot methods reported earlier.<ce:cross-refs refid="bib33 bib37 bib40"><ce:sup>33,37,40</ce:sup>
</ce:cross-refs>
</ce:para>
 </ce:section>
 <ce:section id="cesec30"> <ce:section-title>Tissue Collection and Processing</ce:section-title>
 <ce:para id="para50">The harvesting, fixation, and further processing of the brain tissue specimens were conducted as previously described.<ce:cross-refs refid="bib22 bib41"><ce:sup>22,41</ce:sup>
</ce:cross-refs>
 Briefly, tissue blocks were removed at autopsy from the cingulate cortex and mesencephalon of six DLB and five LBVAD brains, the cerebellar white matter from seven MSA brains, and the insular cortex and globus pallidus from one NBIA1 brain (see <ce:cross-ref refid="tbl1">Table 1</ce:cross-ref>
<ce:float-anchor refid="tbl1"></ce:float-anchor>
). The diagnostic assessment of all cases was performed in concordance with published guidelines.<ce:cross-refs refid="bib42 bib43 bib44"><ce:sup>42–44</ce:sup>
</ce:cross-refs>
 Samples from these brains were fixed by immersion in 70% ethanol with 150 mmol/L NaCl for 24 to 36 hours, and paraffin embedded according to a previously described schedule.<ce:cross-ref refid="bib45"><ce:sup>45</ce:sup>
</ce:cross-ref>
 These blocks were then cut into multiple, near serial, 6-μm sections for immunohistochemical staining.</ce:para>
 </ce:section>
 <ce:section id="cesec40"> <ce:section-title>Antibodies and Immunohistochemistry</ce:section-title>
 <ce:para id="para60">The presence of 3-NT modified substrates in human tissue was detected by immunohistochemistry using the 3-NT pAb (generously provided by Joseph S. Beckman; previously characterized by Beckman et al<ce:cross-ref refid="bib46"><ce:sup>46</ce:sup>
</ce:cross-ref>
 and Ye et al<ce:cross-ref refid="bib47"><ce:sup>47</ce:sup>
</ce:cross-ref>
), and the avidin-biotin complex (ABC) system (Vectastain ABC Elite Kit, Vector Laboratories, Burlingame, CA) with the chromagen 3,3′-diaminobenzidine as previously described.<ce:cross-ref refid="bib48"><ce:sup>48</ce:sup>
</ce:cross-ref>
 Briefly, sections were heated at 60°C for 60 minutes, deparaffinized and hydrated through graded ethanols, rinsed in 0.1 mol/L phosphate-buffered saline (PBS), pH 7.1, and endogenous peroxidases were neutralized with 5. H<ce:inf>2</ce:inf>
O<ce:inf>2</ce:inf>
 in methanol for 20 minutes. Sections were then washed and blocked in PBS containing 10. goat serum and 1% bovine serum albumin for 30 minutes at 37°C. 3-NT pAb was diluted 1:400 in PBS containing 10% goat serum and 1% bovine serum albumin, and incubated at 37°C for 90 minutes. Slides were washed and incubated with biotinylated goat anti-rabbit antibody at 37°C for 40 minutes. Slides were washed and incubated with ABC solution at 37°C for 30 minutes. Bound antibody complexes were visualized with 3,3′-diaminobenzidine followed by a brief wash in distilled water. The sections were then lightly counterstained with hematoxylin, dehydrated, and coverslipped. Negative controls for the 3-NT pAb included preabsorption of this antibody with a 10-fold excess of purified 3-NT and pre-incubation of tissue sections with 100 mmol/L dithionite as described previously.<ce:cross-ref refid="bib48"><ce:sup>48</ce:sup>
</ce:cross-ref>
</ce:para>
 </ce:section>
 <ce:section id="cesec50"> <ce:section-title>Quantitation of GCIs and LBs</ce:section-title>
 <ce:para id="para70">Consecutive 6-μm sections were taken from each of the MSA (cerebellum) or DLB/LBVAD (cingulate cortex) brains and immunostained with either the 3-NT pAb as described above, or a mouse anti-α-syn-specific monoclonal antibody, Syn 202,<ce:cross-ref refid="bib49"><ce:sup>49</ce:sup>
</ce:cross-ref>
 to count the total number of GCIs or LBs in a given field. Immunostaining with the Syn 202 was performed as described previously.<ce:cross-refs refid="bib45 bib50"><ce:sup>45,50</ce:sup>
</ce:cross-refs>
 Briefly, the sections were deparaffinized, hydrated through graded ethanols, treated with 5. H<ce:inf>2</ce:inf>
O<ce:inf>2</ce:inf>
 in methanol, and blocked in 2% donor horse serum in 0.1 mol/L Tris (Tris/donor horse serum) for 5 minutes. Primary incubation was performed with Syn 202 diluted 1:1,500 in Tris/DHS overnight at 4°C. After washing, sections were sequentially incubated with biotinylated secondary antibodies for 1 hour and avidin-horseradish peroxidase complex (Vectastain Standard ABC kit; Vector Laboratories) for 1 hour. Bound antibody complexes were visualized using 3,3′-diaminobenzidine.</ce:para>
 <ce:para id="para80">For GCI quantification, five adjacent medium power (×200. photomicrographs were taken from the MSA cerebellar white-matter tissue sections stained with either the 3-NT pAb or Syn 202 and the total number of GCIs in all five photomicrographs was obtained. For LB quantification, the total number of LBs recognized by each antibody within entire tissue sections of cingulate cortex from DLB and LBVAD cases were counted for each antibody. The percentage of LBs or GCIs labeled with the 3-NT pAb was determined as a ratio of 3-NT pAb inclusion counts over Syn 202 inclusion counts.</ce:para>
 </ce:section>
 </ce:section>
 <ce:section id="cesec60"> <ce:section-title>Results</ce:section-title>
 <ce:section id="cesec70"> <ce:section-title>Immunohistochemical Localization of 3-NT in Neurodegenerative Brain Lesions</ce:section-title>
 <ce:para id="para90">In all of the DLB and LBVAD brain sections (see <ce:cross-ref refid="tbl1">Table 1</ce:cross-ref>
 for a summary of cases studied), the 3-NT pAb robustly stained cortical and nigral LBs, as well as many LNs (<ce:cross-ref refid="fig1">Figure 1, a–c</ce:cross-ref>
<ce:float-anchor refid="fig1"></ce:float-anchor>
). In the substantia nigra pars compacta, the core and peripheral halo of classical LBs were labeled by this antibody (<ce:cross-ref refid="fig1">Figure 1c</ce:cross-ref>
), whereas robust 3-NT immunoreactivity was observed throughout many GCIs in the cerebellar white matter in all MSA brains examined here (<ce:cross-ref refid="fig1">Figure 1, d–f</ce:cross-ref>
), and these 3-NT-positive GCIs were seen in satellite, interfascicular, and perivascular oligodendrocytes.</ce:para>
 <ce:para id="para100">In the NBIA1 brain, the 3-NT pAb immunolabeled LB-like inclusions (<ce:cross-ref refid="fig1">Figure 1, g and h</ce:cross-ref>
) and neuraxonal spheroids (<ce:cross-ref refid="fig1">Figure 1i</ce:cross-ref>
) of the globus pallidus. As in LBs of DLB and LBVAD brains, 3-NT immunoreactivity was seen in the core and halo regions of LB-like inclusions of the NBIA1 brain (<ce:cross-ref refid="fig1">Figure 1g</ce:cross-ref>
), and white-matter GCIs also were extensively immunoreactive for 3-NT (<ce:cross-ref refid="fig1">Figure 1j</ce:cross-ref>
). The specificity of this 3-NT pAb for 3-NT residues was confirmed using control sections treated with dithionite (which reduces 3-NT to 3-aminotyrosine), and by preabsorbing the 3-NT pAb with 3-NT before immunohistochemistry because both control experiments completely abolished the labeling of all pathological inclusions by this antibody (data not shown).</ce:para>
 </ce:section>
 <ce:section id="cesec80"> <ce:section-title>Quantitation of 3-NT Immunoreactive LBs and GCIs</ce:section-title>
 <ce:para id="para110">The percentage of α-syn-positive cortical LBs that were also 3-NT immunoreactive ranged from 61 to 100% (mean, 76.2%) in DLB brains and from 57 to 80% (mean, 67.8%) in LBVAD brains (<ce:cross-ref refid="tbl2">Table 2</ce:cross-ref>
<ce:float-anchor refid="tbl2"></ce:float-anchor>
). Presumably because of section-to-section variation in the number of LBS, one DLB brain had slightly more 3-NT-immunolabeled LBs than those labeled by antibodies to α-syn in adjacent sections, and this case (identified by an asterisk in <ce:cross-ref refid="tbl2">Table 2</ce:cross-ref>
) was assigned a grade of 100%. Further, the percentage of α-syn-positive GCIs in the MSA brains that were 3-NT immunoreactive ranged from 56 to 76% (mean, 65.4%). Finally, there was no apparent relationship between the percentage of 3-NT-positive LBs or GCIs and the severity of the neuropathology, as reflected by the abundance of these α-syn inclusions.</ce:para>
 </ce:section>
 <ce:section id="cesec90"> <ce:section-title>Western Blot Analysis of Nitrated Proteins Recognized by the 3-NT pAb</ce:section-title>
 <ce:para id="para120">α-Syn is the major component of LBs and GCIs, however other proteins such as NF subunits<ce:cross-refs refid="bib41 bib51 bib52"><ce:sup>41,51,52</ce:sup>
</ce:cross-refs>
 and tubulins<ce:cross-refs refid="bib53 bib54"><ce:sup>53,54</ce:sup>
</ce:cross-refs>
 are prominent constituents of LBs and GCIs, respectively. Because it is plausible that the 3-NT pAb could recognize a variety of nitrated proteins, Western blot analysis was used to compare the relative specificity of this antibody for these proteins after <ce:italic>in vitro</ce:italic>
 nitration. Human α-syn, bovine microtubule-derived tubulins, as well as mouse NFL and bovine NFM and NFH were exposed under identical conditions to the same quantity of peroxynitrite in the presence of CO<ce:inf>2</ce:inf>
. As shown in <ce:cross-ref refid="fig2">Figure 2</ce:cross-ref>
<ce:float-anchor refid="fig2"></ce:float-anchor>
, the immunoreactivity for <ce:italic>in vitro-</ce:italic>
 nitrated α-syn was significantly more intense than that for <ce:italic>in vitro-</ce:italic>
 nitrated tubulins or NF proteins. This dramatic difference may be because of more extensive nitration of α-syn, or greater affinity of this 3-NT pAb for nitrated α-syn which is known to be nitrated <ce:italic>in vitro</ce:italic>
 at all four of its tyrosine residues, primarily because of the random coil conformation that this protein assumes in solution.<ce:cross-ref refid="bib40"><ce:sup>40</ce:sup>
</ce:cross-ref>
 Indeed, other proteins may assume alternative secondary structures that confer a selective susceptibility of their tyrosine residues to nitration, as in NFL.<ce:cross-ref refid="bib55"><ce:sup>55</ce:sup>
</ce:cross-ref>
 Notably, the higher molecular mass species of α-syn seen in <ce:cross-ref refid="fig2">Figure 2</ce:cross-ref>
 probably reflect peroxynitrite-induced <ce:italic>o-o</ce:italic>
′-dityrosine cross-link formation because α-syn has been show to be modified by this reaction more readily than other proteins.<ce:cross-ref refid="bib40"><ce:sup>40</ce:sup>
</ce:cross-ref>
</ce:para>
 </ce:section>
 </ce:section>
 <ce:section id="cesec100"> <ce:section-title>Discussion</ce:section-title>
 <ce:para id="para130">Although evidence that oxidative and nitrative modifications occur in several different neurodegenerative diseases continues to accumulate, it remains unclear if these modifications play a mechanistic role in brain degeneration, or if they deleteriously affect neurons and glia in these disorders. Similarly, although many signature lesions of a large number of distinct neurodegenerative diseases are composed of abnormal aggregates of different brain proteins,<ce:cross-ref refid="bib56"><ce:sup>56</ce:sup>
</ce:cross-ref>
 it remains incompletely understood how they compromise the function and viability of neurons and glia. Because oxidative and nitrative injury may play a mechanistic role in the pathogenesis of one or more of these signature lesions, the detection of 3-NT immunoreactivity in some of these pathological protein aggregates by a limited number of published studies implies that components of these lesions have been modified by nitrative and oxidative injury.<ce:cross-refs refid="bib13 bib14 bib15"><ce:sup>13–15</ce:sup>
</ce:cross-refs>
 Thus, to extend previous reports of the presence of 3-NT-modified residues in studies that focused exclusively on Alzheimer's disease neurofibrillary tangles and LBs in Parkinson's disease brains,<ce:cross-refs refid="bib13 bib14 bib15"><ce:sup>13–15</ce:sup>
</ce:cross-refs>
 we conducted the studies described here which showed that protein nitration is not limited to the LBs of Parkinson's disease. Indeed, we demonstrated that this also occurs in LBs of DLB and LBVAD brains, as well as in NBIA1 LB-like inclusions. The presence of 3-NT immunoreactivity also was demonstrated in all other α-syn rich neuropathological hallmarks of MSA, NBIA1, DLB, or LBVAD (ie, LNs, GCIs, neuronal cytoplasmic inclusions, and neuraxonal spheroids) and our quantitative analysis showed that the majority of these inclusions contain 3-NT modified protein.</ce:para>
 <ce:para id="para140">Taken together with previous observations, our studies suggest that α-syn is nitrated in the α-syn lesions detected here by the 3-NT pAb. The abundance of α-syn in LBs and GCIs and the recent observation that α-syn is an excellent substrate for nitration<ce:cross-ref refid="bib40"><ce:sup>40</ce:sup>
</ce:cross-ref>
 provide compelling support for this view. Further, because we also showed that nitrated α-syn was far more intensely labeled by the 3-NT pAb than any of the other nitrated proteins examined here by Western blot, it is highly likely that α-syn is the major 3-NT-modified protein in the lesions we studied. Nonetheless, additional studies are needed to confirm this using complementary methods and additional synucleinopathy brains.</ce:para>
 <ce:para id="para150">Because the majority (57 to 100%) of the inclusions counted here, (ie, LBs and GCIs), contained 3-NT immunoreactivity, it is tempting to speculate that nitrative or oxidative damage may cause aggregation of proteins to form these inclusions. However, not all inclusions were labeled by the 3-NT pAb and this may be because of the fact that the generation of 3-NT by nitration is enzymatically reversible, and denitration of 3-NT may occur throughout an extended period of time if normal cellular reductive capacities are re-established. Thus, the generation of additional antibodies that specifically recognize the more stable <ce:italic>o-o</ce:italic>
′-dityrosine modification induced by nitration may demonstrate the presence of nitrative injury in all of these α-syn inclusions.</ce:para>
 <ce:para id="para160">The effects of α-syn nitration are undetermined, but it is possible that nitration may render α-syn more resistant to proteolysis or alter other properties of this synaptic protein thereby playing a mechanistic role in the formation of α-syn lesions as well as in the onset/progression of synucleinopathies. Nitrating species also may contribute to the pathogenesis of α-syn lesions by oxidizing tyrosine residues to form <ce:italic>o-o</ce:italic>
′-dityrosine resulting in the covalent cross-linking of α-syn and the formation of stable α-syn polymers.<ce:cross-ref refid="bib40"><ce:sup>40</ce:sup>
</ce:cross-ref>
 Indeed, <ce:italic>o-o</ce:italic>
′-dityrosine formation may be more damaging than the 3-NT modification because this alteration may be reversed enzymatically whereas <ce:italic>o-o</ce:italic>
′-dityrosine cross-linking is more stable and it may retard or prevent the removal of abnormal protein aggregates.<ce:cross-refs refid="bib57 bib58"><ce:sup>57,58</ce:sup>
</ce:cross-refs>
</ce:para>
 <ce:para id="para170">These uncertainties not withstanding, based on the data described here, together with evidence that <ce:italic>o-o</ce:italic>
′-dityrosine cross-linking of α-syn leads to the formation of stable α-syn polymers,<ce:cross-ref refid="bib40"><ce:sup>40</ce:sup>
</ce:cross-ref>
 we suggest that loss of neuronal or glial oxidative protective mechanisms may have deleterious effects on the normal functions or metabolism of α-syn and thereby contribute to the onset/progression of neurodegenerative synucleinopathies. Thus, further studies of the role of oxidative and nitrative injury in mechanisms underlying these and other neurodegenerative disorders may lead to the identification of therapeutic targets for the prevention or reversal of these diseases.</ce:para>
 </ce:section>
 </ce:sections>
 <ce:acknowledgment> <ce:section-title>Acknowledgements</ce:section-title>
 <ce:para id="para180">We thank Dr. Walter Mushynski for the gift of the NFL-pET-23d plasmid and the families of the patients that make this research possible.</ce:para>
 </ce:acknowledgment>
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<mods version="3.6"><titleInfo><title>Widespread Nitration of Pathological Inclusions in Neurodegenerative Synucleinopathies</title>
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<titleInfo type="alternative" contentType="CDATA"><title>Widespread Nitration of Pathological Inclusions in Neurodegenerative Synucleinopathies</title>
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<name type="personal"><namePart type="given">John E.</namePart>
<namePart type="family">Duda</namePart>
<role><roleTerm type="text">author</roleTerm>
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</name>
<name type="personal"><namePart type="given">Benoit I.</namePart>
<namePart type="family">Giasson</namePart>
<role><roleTerm type="text">author</roleTerm>
</role>
</name>
<name type="personal"><namePart type="given">Qiping</namePart>
<namePart type="family">Chen</namePart>
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</name>
<name type="personal"><namePart type="given">Tamar L.</namePart>
<namePart type="family">Gur</namePart>
<role><roleTerm type="text">author</roleTerm>
</role>
</name>
<name type="personal"><namePart type="given">Howard I.</namePart>
<namePart type="family">Hurtig</namePart>
<role><roleTerm type="text">author</roleTerm>
</role>
</name>
<name type="personal"><namePart type="given">Matthew B.</namePart>
<namePart type="family">Stern</namePart>
<role><roleTerm type="text">author</roleTerm>
</role>
</name>
<name type="personal"><namePart type="given">Steven M.</namePart>
<namePart type="family">Gollomp</namePart>
<role><roleTerm type="text">author</roleTerm>
</role>
</name>
<name type="personal"><namePart type="given">Harry</namePart>
<namePart type="family">Ischiropoulos</namePart>
<role><roleTerm type="text">author</roleTerm>
</role>
</name>
<name type="personal"><namePart type="given">Virginia M.-Y.</namePart>
<namePart type="family">Lee</namePart>
<role><roleTerm type="text">author</roleTerm>
</role>
</name>
<name type="personal"><namePart type="given">John Q.</namePart>
<namePart type="family">Trojanowski</namePart>
<affiliation>E-mail: trojanowmail.med.upenn.edu</affiliation>
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<dateValid encoding="w3cdtf">2000-08-03</dateValid>
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<abstract>Reactive nitrogen species may play a mechanistic role in neurodegenerative diseases by posttranslationally altering normal brain proteins. In support of this hypothesis, we demonstrate that an anti-3-nitrotyrosine polyclonal antibody stains all of the major hallmark lesions of synucleinopathies including Lewy bodies, Lewy neurites and neuraxonal spheroids in dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, and neurodegeneration with brain iron accumulation type 1, as well as glial and neuronal cytoplasmic inclusions in multiple system atrophy. This antibody predominantly recognized nitrated -synuclein when compared to other in vitro nitrated constituents of these pathological lesions, such as neurofilament subunits and microtubules. Collectively, these findings imply that -synuclein is nitrated in pathological lesions. The widespread presence of nitrated -synuclein in diverse intracellular inclusions suggests that oxidation/nitration is involved in the onset and/or progression of neurodegenerative diseases.</abstract>
<note>Supported by grants from the National Institutes of Health and by a Pioneer Award from the Alzheimer's Association. B. I. G. is the recipient of a fellowship from the Human Frontier Science Program Organization.</note>
<note type="content">Section title: Short Communications</note>
<note type="content">Figure 1: Immunostaining with the 3-NT pAb in sections of DLB, LBVAD, MSA, and NBIA1 brains. a and b: 3-NT immunostaining of -syn lesions in the cingulate cortex of DLB and LBVAD brains, respectively. The insert in a shows a high-power magnification of a typical 3-NT-positive LB and LN from the same section. c: Intense 3-NT immunostaining throughout a classical LB in a pigmented substantia nigra pars compacta neuron of an LBVAD brain. df: Robust 3-NT immunostaining is seen in multiple GCIs throughout cerebellar white matter of three different MSA brains. In the NBIA1 brain, intense 3-NT immunoreactivity is seen in LB-like inclusions of the globus pallidus (g and h), as well as in neuraxonal spheroids (i), and GCIs from the insular cortex (j). Scale bars, 30 m (a, b, df)and 10 m (inset in a, c, gj).</note>
<note type="content">Figure 2: Western blot analysis of 3-NT pAb antibody. A: Coomassie-stained gel of in vitro nitrated -syn, tubulin, NFL, NFM, and NFH. Five g of each protein were resolved by electrophoresis on separate lanes of a discontinuous 6 to 10 to 12 sodium dodecyl sulfate-polyacrylamide gel. The arrow on the left denotes monomeric -syn. B: In Western blots the 3-NT pAb variably recognizes each of the nitrated proteins but none are as intensely immunoreactive as nitrated -syn. Note the robust recognition of monomeric -syn as well as higher oligomeric -syn species by this antibody. The arrows in B identify the far less intensely labeled immunobands for each of the other proteins. Fifty ng of each protein were resolved by electrophoresis on a discontinuous 6 to 10 to 12 sodium dodecyl sulfate-polyacrylamide gel. After electrophoretic transfer to nitrocellulose membrane, the blot was blocked with 5 skimmed milk, sequentially incubated with the 3-NT pAb and anti-rabbit-horseradish peroxidase-conjugated antibody and developed with enhanced luminol reagents (Dupont-New England Nuclear). The position of the molecular weight markers are indicated on the left.</note>
<note type="content">Table 1: Case Demographics</note>
<note type="content">Table 2: Percentage of 3-NT-Positive Inclusions</note>
<subject><genre>Article category</genre>
<topic>Nitration of Pathological Inclusions</topic>
</subject>
<relatedItem type="host"><titleInfo><title>The American Journal of Pathology</title>
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<titleInfo type="abbreviated"><title>AJPA</title>
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<genre type="Journal">journal</genre>
<originInfo><dateIssued encoding="w3cdtf">200011</dateIssued>
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<identifier type="ISSN">0002-9440</identifier>
<identifier type="PII">S0002-9440(10)X6127-2</identifier>
<part><detail type="volume"><number>157</number>
<caption>vol.</caption>
</detail>
<detail type="issue"><number>5</number>
<caption>no.</caption>
</detail>
<extent unit="issue pages"><start>1415</start>
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<extent unit="pages"><start>1439</start>
<end>1445</end>
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<identifier type="istex">9DCA7685D30C7D05A92A3C635DCF14ACC1A7D7F5</identifier>
<identifier type="DOI">10.1016/S0002-9440(10)64781-5</identifier>
<identifier type="PII">S0002-9440(10)64781-5</identifier>
<accessCondition type="use and reproduction" contentType="">© 2000American Society for Investigative Pathology</accessCondition>
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<recordOrigin>American Society for Investigative Pathology, ©2000</recordOrigin>
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Widespread Nitration of Pathological Inclusions in Neurodegenerative Synucleinopathies

Widespread Nitration of Pathological Inclusions in Neurodegenerative Synucleinopathies

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