Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease
Identifieur interne : 002E81 ( Main/Corpus ); précédent : 002E80; suivant : 002E82Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease
Auteurs : Etienne Hirsch ; Ann M. Graybiel ; Yves A. AgidSource :
- Nature [ 0028-0836 ] ; 1988-07-28.
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DOI: 10.1038/334345a0
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title>Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease</title><author><name sortKey="Hirsch, Etienne" sort="Hirsch, Etienne" uniqKey="Hirsch E" first="Etienne" last="Hirsch">Etienne Hirsch</name></author><author><name sortKey="Graybiel, Ann M" sort="Graybiel, Ann M" uniqKey="Graybiel A" first="Ann M." last="Graybiel">Ann M. Graybiel</name></author><author><name sortKey="Agid, Yves A" sort="Agid, Yves A" uniqKey="Agid Y" first="Yves A." last="Agid">Yves A. Agid</name></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:F760B501C9D54598B9FF7BD547A14192499296A9</idno><date when="1988" year="1988">1988</date><idno type="doi">10.1038/334345a0</idno><idno type="url">https://api.istex.fr/document/F760B501C9D54598B9FF7BD547A14192499296A9/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">002E81</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease</title><author><name sortKey="Hirsch, Etienne" sort="Hirsch, Etienne" uniqKey="Hirsch E" first="Etienne" last="Hirsch">Etienne Hirsch</name></author><author><name sortKey="Graybiel, Ann M" sort="Graybiel, Ann M" uniqKey="Graybiel A" first="Ann M." last="Graybiel">Ann M. Graybiel</name></author><author><name sortKey="Agid, Yves A" sort="Agid, Yves A" uniqKey="Agid Y" first="Yves A." last="Agid">Yves A. Agid</name></author></analytic><monogr></monogr><series><title level="j">Nature</title><idno type="ISSN">0028-0836</idno><imprint><publisher>Nature Publishing Group</publisher><date type="published" when="1988-07-28">1988-07-28</date><biblScope unit="volume">334</biblScope><biblScope unit="issue">6180</biblScope><biblScope unit="page" from="345">345</biblScope><biblScope unit="page" to="348">348</biblScope></imprint><idno type="ISSN">0028-0836</idno></series><idno type="istex">F760B501C9D54598B9FF7BD547A14192499296A9</idno><idno type="DOI">10.1038/334345a0</idno><idno type="ArticleID">334345a0</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0028-0836</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader></TEI><istex><corpusName>nature</corpusName><author><json:item><name>Etienne Hirsch</name></json:item><json:item><name>Ann M. Graybiel</name></json:item><json:item><name>Yves A. Agid</name></json:item></author><language><json:string>unknown</json:string></language><abstract>In idiopathic Parkinson's disease massive cell death occurs in the dopamine-containing substantia nigra1,24. A link between the vulnerability of nigral neurons and the prominent pigmentation of the substantia nigra, though long suspected, has not been proved2. This possibility is supported by evidence that N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its metabolite MPP+, the latter of which causes destruction of nigral neurons, bind to neuromelanin3,4. We have directly tested this hypothesis by a quantitative analysis of neuromelanin-pigmented neurons in control and parkinsonian midbrains. The findings demonstrate first that the dopamine-containing cell groups of the normal human midbrain differ markedly from each other in the percentage of neuromelanin-pigmented neurons they contain. Second, the estimated cell loss in these cell groups in Parkinson's disease is directly correlated (r = 0.97, P = 0.0057) with the percentage of neuromelanin-pigmented neurons normally present in them. Third, within each cell group in the Parkinson's brains, there is greater relative sparing of non-pigmented than of neuromelanin-pigmented neurons. This evidence suggests a selective vulnerability of the neuromelanin-pigmented subpopulation of dopamine-containing mesencephalic neurons in Parkinson's disease.</abstract><qualityIndicators><score>2.605</score><pdfVersion>1.4</pdfVersion><pdfPageSize>581.102 x 793.701 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>0</keywordCount><abstractCharCount>1318</abstractCharCount><pdfWordCount>17</pdfWordCount><pdfCharCount>104</pdfCharCount><pdfPageCount>4</pdfPageCount><abstractWordCount>174</abstractWordCount></qualityIndicators><title>Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease</title><genre><json:string>other</json:string></genre><host><volume>334</volume><pages><last>348</last><first>345</first></pages><issn><json:string>0028-0836</json:string></issn><issue>6180</issue><genre></genre><language><json:string>unknown</json:string></language><title>Nature</title></host><categories><wos><json:string>MULTIDISCIPLINARY SCIENCES</json:string></wos></categories><publicationDate>1988</publicationDate><copyrightDate>1988</copyrightDate><doi><json:string>10.1038/334345a0</json:string></doi><id>F760B501C9D54598B9FF7BD547A14192499296A9</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/F760B501C9D54598B9FF7BD547A14192499296A9/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/F760B501C9D54598B9FF7BD547A14192499296A9/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/F760B501C9D54598B9FF7BD547A14192499296A9/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a">Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Nature Publishing Group</publisher><availability><p>NATURE</p></availability><date>1988</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease</title><author><persName><forename type="first">Etienne</forename><surname>Hirsch</surname></persName></author><author><persName><forename type="first">Ann M.</forename><surname>Graybiel</surname></persName></author><author><persName><forename type="first">Yves A.</forename><surname>Agid</surname></persName></author></analytic><monogr><title level="j">Nature</title><idno type="pISSN">0028-0836</idno><imprint><publisher>Nature Publishing Group</publisher><date type="published" when="1988-07-28"></date><biblScope unit="volume">334</biblScope><biblScope unit="issue">6180</biblScope><biblScope unit="page" from="345">345</biblScope><biblScope unit="page" to="348">348</biblScope></imprint></monogr><idno type="istex">F760B501C9D54598B9FF7BD547A14192499296A9</idno><idno type="DOI">10.1038/334345a0</idno><idno type="ArticleID">334345a0</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>1988</date></creation></profileDesc><revisionDesc><change when="1988-06-07">Registration</change><change when="1988-07-28">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/F760B501C9D54598B9FF7BD547A14192499296A9/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus nature, element headerx not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0"</istex:xmlDeclaration><istex:docType PUBLIC="-//NPG//DTD headerx//EN" URI="headerx.dtd" name="istex:docType"></istex:docType><istex:document><headerx>
<ArticleIdList><ArticleId>334345a0</ArticleId></ArticleIdList><pubfm><jtl>Nature</jtl><vol>334</vol><iss>6180</iss><idt>19880728</idt><categ id="lt"></categ><pp><spn>345</spn><epn>348</epn></pp><issn>0028-0836</issn><cpg><cpy>1988</cpy><cpn>Nature Publishing Group</cpn></cpg><doi>10.1038/334345a0</doi></pubfm><fm><atl>Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease</atl><aug><au><fnm>Etienne</fnm><snm>Hirsch</snm><inits>E.</inits><super>*</super></au><au><fnm>Ann M.</fnm><snm>Graybiel</snm><inits>A. M.</inits><super>†‡</super></au><au><fnm>Yves A.</fnm><snm>Agid</snm><inits>Y. A.</inits><super>*</super></au><aff><super>*</super> INSERM U289, Laboratoire de Medecine Experimentale, Hôpital de la Salpêtrière, 47 Bd. de I'Hôpital, 75013, Paris, France </aff><aff><super>†</super> Department of Brain and Cognitive Sciences, Whitaker College, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA</aff><aff><super>‡</super> To whom correspondence should be addressed.</aff></aug><hst><re day="13" month="4" year="na"></re><acc day="7" month="6" year="1988"></acc></hst><fp><p>In idiopathic Parkinson's disease massive cell death occurs in the dopamine-containing substantia nigra<super>1,24</super>. A link between the vulnerability of nigral neurons and the prominent pigmentation of the substantia nigra, though long suspected, has not been proved<super>2</super>. This possibility is supported by evidence that N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its metabolite MPP<super>+</super>, the latter of which causes destruction of nigral neurons, bind to neuromelanin<super>3,4</super>. We have directly tested this hypothesis by a quantitative analysis of neuromelanin-pigmented neurons in control and parkinsonian midbrains. The findings demonstrate first that the dopamine-containing cell groups of the normal human midbrain differ markedly from each other in the percentage of neuromelanin-pigmented neurons they contain. Second, the estimated cell loss in these cell groups in Parkinson's disease is directly correlated (<i>r</i> = 0.97, <i>P</i> = 0.0057) with the percentage of neuromelanin-pigmented neurons normally present in them. Third, within each cell group in the Parkinson's brains, there is greater relative sparing of non-pigmented than of neuromelanin-pigmented neurons. This evidence suggests a selective vulnerability of the neuromelanin-pigmented subpopulation of dopamine-containing mesencephalic neurons in Parkinson's disease.</p></fp></fm><bdy>
Three sets of neurons were studied in autopsy material from four patients who died with a diagnosis of Parkinson's disease, and from three people without known neurological disease. These were catecholamine-containing neurons identified by tyrosine-hydroxylase (TH)*) immunohistochemistry, neuromelanin-pigmented (NM*) neurons detected in haematoxylin-eosin stained sections and acetylcholinesterase (AChE)-positive neurons observed by acetylthiocholine iodide histochemistry. A similar analysis was made in brains from three patients who died with a diagnosis of progressive supranuclear palsy (PSP), another degenerative parkinsonian syndrome5. The numbers and locations of neurons of each type were recorded with a computerized plotting system for sets of serial sections through the midbrain (see Fig. 1). Maps were also made of any NM"4", TH~ neurons observed in the TH-immunostained sections. Total numbers of neurons of each type were compared for each region and the percentage of NM* neurons per region was calculated (see legend of Fig. 1).
In the normal midbrains (Fig. 2), TH* neurons were most densely distributed within the substantia nigra pars compacta, but many also appeared in the substantia nigra pars lateralis, in tegmental cell group A8, in cell group A10 and the paramedian tegmentum, and in the central grey substance, all of which are known to contain dopaminergic neurons6"9, as well as farther caudally, in the noradrenergic locus coeruleus. NM* neurons, though densely concentrated in the substantia nigra pars compacta and in the locus coeruleus, were sparse in the other regions containing TH* cells. They were only rarely detectable in the central grey substance.
When chart ings from Parkinson's brains were compared to those from controls (Fig. 2), it was clear that many non-nigral catecholaminergic neurons were present in the Parkinson's mid-brains. Loss of TH* neurons was massive (77%) in the substantia nigra pars compacta but almost undetectable (3%) in the central grey substance. In cell group A8 and in the AlO-paramedian tegmental region, the loss of TH4 neurons was intermediate (43% and 48%, respectively). A regression analysis (Fig. 3) showed a strong correlation between these estimates of catecholaminergic cell loss in the dopamine-containing cell groups in Parkinson's disease and the numbers of NM+ neurons in these cell groups in the control brains (Table 1). The correlation curve was linear (P = 0.0057), had an r value of 0.97, and showed a slope of 1.06 and an x-intercept of 4.5.
An analysis by cell group of the surviving neurons in the Parkinson's midbrains is summarized in Table 2. In the A8-A9-A10 cell complex, the relative survival of the non-pigmented subpopulation was most marked for the substantia nigra pars compacta and for tegmental cell group A8 (about three times that of the general TH* population) and was moderate (xl.5) for the AlO-paramedian tegmental region and substantia nigra pars lateralis. In the central grey substance, the estimated
survival of non-pigmented cells was 25 times that of the pigmented cells.
Fig. 1 Distribution of TH"1" neurons (black dots) in a representative tranverse section through the midbrain of a control specimen shown to illustrate procedures for quantitative plotting. The five catecholamine-containing regions analysed at this level are delimited by the rectilinear outlines as follows: the substantia nigra pars compacta (SNpc); the substantia nigra pars lateralis (SNpl); the medioventral part of the midbrain corresponding to the A10 cell group together with the adjoining paramedian and median midbrain tegmentum (M); the central grey substance (CGS); and the remaining part of the tegmentum dorsal to the medial lemniscus, corresponding to catecholamine-containing cell group A8 (A8). The more caudally situated locus coeruleus (not shown) was analysed only through its rostral third which extended 5,760 jj,m from the rostral pole of the nucleus (identified in TH-immunostained and haematoxylin and eosin-stained sections). For each brain, x-y plots of every cell of each type analysed were obtained for regularly spaced (1,440 |xm) transverse sections using a computer-assisted microscope system that allowed each cell to be plotted once and only once. Sections were chosen from an anterior level through the subthalamic nucleus to a posterior level through the midlength of the locus coeruleus. Plots were made at xlOO. A grid adjustable in size to correct for relative shrinkage from one brain to another (and normalized for one control brain) was superimposed on the plots, and plots and corresponding grids were then printed. The images of serially-adjoining sections stained for AChE were projected onto each printed drawing. Landmarks such as the red nucleus (RN) and the medial lemniscus (ML), and regions of high or low AChE staining were drawn on the plots to help delimit the anatomical regions. For each region so delimited for each section, the total number of neurons of each type was counted. These values were then plotted against the cumulative distance between the sections, and the surface area under this curve gave an estimate of the total number of neurons per region from its rostral to caudal extent (see ref. 22).
Table 1 Neuronal populations in catecholaminergic cell groups in control, parkinsonian and PSP brains
NM+ cells in Decrease TH+ cells Decrease TH+ cells TH~ NM+ cells in TH~ NM+ cells
Estimated TH+ controls in Parkinsons in PSP in Parkinson's in PSP
Cell group cells in controls (%) (%) (%) (%) (%)
SNpc 213,186 84 77 84 17 64
SNpl 5,451 49 31 82 5 38
A8 38,461 52 43 65 0 0
M 32,314 51 48 76 0 19
CGS 6,836 2 3 52 0 0
Ic 15,488 111 55 -7 12 3
TH+, TH-immunoreactive neurons; NM+, neuromelanin-pigmented neurons; TH+ NM"*", NM* TH-negative neurons. Values are % of total cells found in TH-immunostained sections of control (aged 83 ±3.3 years, postmortem delays 12 ±6 hours), parkinsonian (aged 65 ± 1 years, postmortem delays 27 ±8 h) and PSP (aged 73 ±7 years, postmortem delays 25 ± 10 h) brains. The Parkinson's and PSP cases had no other known neurological defects except for one case of Parkinson's with marked intellectual impairment. For the parkinsonian and PSP brains, the NM+ values are the difference between the number of TH'NM* cells in the TH-immunostained sections and the number of NM+ cells counted in the haematoxylin-eosin stained sections. This avoided the possibility of including as NM+ neurons, dying cells or cells that do not normally express neuromelanin pigmentation (see text), and was done to obtain the most accurate estimate possible of catecholamine-containing pigmented neurons. No such TH~NM+ neurons were seen in the control brains and no correlation was found between their appearance and the postmortem delays before processing of the brains. The fact that no TH~NM+ neurons appeared in the control brains suggested that the TH-immunostaining did not yield large numbers of false negatives. In the diseased brains only if false negatives were unevenly distributed among different cell groups or among NM"*" and NM~ neurons would our assessments of relative sparing have been influenced. For the PD-control comparisons, relative sparing of NM~ neurons in all dopaminergic cell groups was x3.2 with the correction and x2.5 uncorrected. The total number of neurons in the five dopaminergic regions studied (see Fig. 1) and in the noradrenergic locus coeruleus (Ic) was estimated for each region as described in the legend of Fig. 1. The percentage of NM~*~ cells in controls was defined as the ratio of the number of NM"1" neurons to TH"1" neurons for each region. The percentage decrease of TH+ cells for each region was defined as described in the legend for Fig. 3. The percentage of TH'NM"*" cells present in the parkinsonian and PSP material was defined as the ratio between the number of TH~~NM+ neurons in the diseased brains, and the number of TH+ neurons in control brains for each region, expressed as a percentage.
In the PSP midbrains, a correlation between the relative loss of TH+ neurons in each of these cell groups and the estimates of their normal content of NM+ neurons was also apparent (Fig. 3) but it was less pronounced (P = 0.0483). The correlation curve was linear (r = 0.86, slope of 1.9) with an x-intercept of 54.32. Among surviving neurons, there was marked sparing of non-pigmented neurons relative to the general TH"1" population in all regions analysed except the AlO-paramedian tegmental complex.
In contrast to these findings for the dopaminergic cell groups of the midbrain, there was no clear link between neuromelanin content and cell death in the locus coeruleus either in Parkinson's disease or in PSP (Fig. 3). Our measurements for this nucleus were limited, however, because only neurons in its anterior part could be counted (see legend of Fig. 1). We were also unable to find a consistent relationship (1) between the amount of cell death in any of the mesencephalic catecholaminergic cell groups in Parkinson's disease and PSP and the estimated total number of TH+ r AChE+ eurons in these cell groups, or (2) between cell loss in the diseased brains and either postmortem delay before dissection or age at death.
These findings suggest that, within the entire population of dopamine-containing neurons in the midbrain, those characterized by neuromelanin pigmentation may be differentially vulnerable in Parkinson's disease and PSP. For the Parkinson's mid-brains the correlation was simple and direct: the greater the number of pigmented neurons normally present in the dopaminergic cell groups, the larger the loss of neurons in these cell groups in the diseased brains. Moreover, within each cell group, non-pigmented neurons were spared relative to the total population of TH"1" neurons and relative to the population of pigmented neurons. For the PSP midbrains the findings also pointed to a relation between neuromelanin pigmentation and cell death in cell groups other than the AlO-paramedian region, but suggested that additional cytotoxic factors were involved. A third type of cell, not observed in the control midbrains, was identified in the Parkinson's and PSP midbrains by the presence of neuromelanin pigment in the absence of detectable
TH-immunoreactivity (Table 1). These pigmented TH-negative neurons may represent dying neurons that once contained TH; alternatively, they may form a special subset of melanized neurons unique to the parkinsonian midbrains.
Fig. 2 Plots of TH+ neurons (above) and NM+ neurons (below) for serially-adjoining pairs of transverse sections through the nigral complex of a normal brain (control), and brains from parkinsonian patients with a diagnosis of Parkinson's disease or PSP. TH+ neurons were charted as described in Fig. 1 from 40 u,m transverse sections immunostained with an anti-serum against tyrosine hydroxylase (Eugene Tech.; dilution 1:120) by a double-bridge per-oxidase anti-peroxidase technique23 (reagents from Sternberger-Meyer). NM+ neurons were plotted from serially-adjacent sections stained by haematoxylin-eosin. Only neurons containing brown neuromelanin pigment detectable with the light microscope (xlOO) were plotted. The pairs of sections illustrated show the distinct difference in the distribution of TH+ and NM+ neurons in the control midbrains: the majority of TH+ neurons in the ventral mid-brain were also NM+, whereas most of the TH+ neurons in the dorsal midbrain lacked neuromelanin. The pairs of sections from the parkinsonian brains show the sharp decrease in the number of TH+ cells and NM+ cells observed ventrally in both Parkinson's and PSP midbrains. In the dorsal neuromelanin-poor part of the midbrain, many TH+ neurons remain. These results were confirmed quantitatively as shown in Tables 1 and 2. RN, red nucleus; CP, cerebral peduncle.
Fig. 3 Linear regression analysis illustrating correlation between the percentage of NM+ neurons (estimated as
described in Table 1 legend) in each catecholaminergic region analysed (ordinate) and the percentage decrease
in the number of TH+ neurons in these regions (abscissa).Left: data for Parkinson's brains. Right: data for PSP
brains. The cell loss for the Parkinson's and PSP brains was estimated by the ratios between the numbers of TH+
neurons in each region in the diseased brains and the corresponding numbers in the control brains, expressed
as percentages. The correlation curves were calculated for the five dopaminergic regions (black dots). Values for the
only supposed noradrenergic region, the locus coeruleus (Ic, data represented as open circles), are shown on the
charts but were not included in the regression analysis. For the Parkinson's midbrains, the correlation followed
a positive linear regression (slope 1.06, x intercept 4.50, P - 0.0057). The observed value for the locus coeruleus
was more than three standard deviations away from the regression line for the dopaminergic cell groups. For the PSP midbrains the values were r = 0.86, slope =1.9, x intercept = 54.32, P = 0.483.
The distinctions we drew between the neuromelanin-positive and neuromelanin-negative cells were based on the presence or absence of visible pigmentation. It is possible that neurons without detectable pigment contained brown neuromelanin at levels below the threshold for light microscopic detection, or contained other molecular forms of neuromelanin not visible as pigment2. A quantitative analysis with neuromelanin-specific staining is clearly required. Nevertheless, our findings with pigmentation as the marker for neuromelanin suggest that mechanisms underlying cell death in Parkinson's disease are related either directly to the presence of a threshold amount of neuromelanin in the affected cells or to a covariant factor, either intracellular or extracellular.
This conclusion is compatible with three main lines of evidence. First, the biochemical pathways involved in the synthesis of neuromelanin (including its derivation from dopamine) lead to the production of toxic free radicals10. Second, neuromelanin binds many drugs4*11 and among these is the agent MPP+ which is thought to produce degeneration of nigral neurons in man and in other species12"14. Third, in the normal substantia nigra, cell death appears to be related to the content of neuromelanin per cell15. Both Parkinson's and PSP are progressive diseases, so that neuromelanin-linked factors could build up with time to toxic concentrations. Preferential neurotoxicity of melanized neurons clearly does not exclude other factors in parkinsonian syndromes contributing to death of both pigmented and non-pigmented neurons16.
In our analysis, the single exception to the tight correlation between neuromelanin-pigmentation and the cell loss in catecholaminergic midbrain cell-groups was for the norepine-
phrine-containing locus coeruleus. This observation, though limited to the rostral locus coeruleus, raises the possibility that the correlation found between melanization and cell death was specific for the class of mesencephalic catecholaminergic neurons that contain dopamine.
Table 2
Percent survival of cell types in Parkinson's disease and PSP relative to control values
Parkinson's disease PSP
TH+ NM+ NM- TH+ NM+ NM~
Cell group cells cells cells cells cells cells
SNpc 24 18 52 16 10 43
SNpl 69 56 81 18 15 20
A8 57 29 87 35 19 53
M 52 43 61 24 35 13
COS 97 4 99 48 0 49
TH* and NM+ neurons were counted as described in Table 1 legend and numbers of non-pigmented TH+ neurons (NM~, were estimated as (number of TH~) minus (number of NM+). Values are expressed as percentages relative to the total population of TH+ neurons in control brains. There is greater survival of non-pigmented cells than pigmented cells in all five regions in Parkinson's disease. In the PSP brains, there is greater survival of non-pigmented than pigmented neurons in all of these cell groups except the AlO-paramedian tegmental region (M). Abbreviations are as in Fig. 1.
It is important to note that the topography of cell-loss in the Parkinson's brains is consistent with cell position being an aetiologic factor linked to the cellular pigmentation marker. The individual catecholamine-containing cell-groups of the mid-brain are known to have different efferent projections8*9'17'18. If the initial onslaught of the disease process were at the axon terminals of these neurons rather than at their perikarya, such differential projections could be directly related to the incidence of neurotoxicity. For technical reasons we did not determine whether subdivisions within the substantia nigra pars compacta were differentially affected, but this is a reasonable expectation. In MPTP intoxication in the monkey selective sparing of parts of A8-A9-A10 cell complex and the lateral or ventral substantia nigra has been claimed19'20, and in the dog, MPTP-induced degeneration of nigrostriatal fibres has been reported to start with fibres that innervate the extrastriosomal matrix21.
This work was funded by the Seaver Institute, the Edith C. Blum Foundation, the Tourette Syndrome Association, the McKnight Foundation, the Whitaker Foundation, the Fondation Simone et Cino del Ducca, and INSERM. We thank Dr J. R. Lackner for his advice on data analysis, Dr D. Whittington for his help with the image-analysis system, and Drs J. J. Hauw, C. Duyckaerts, P. Cervera and F. Javoy-Agid for their help in obtaining the brain specimens.
</bdy>
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D., Jenner, P. & Teychenne, P.) <ppf>33</ppf>–<ppf>66</ppf> (Raven, New York, <cd year="1986">1986</cd>).</reftxt></bib></bibl></bm></headerx></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease</title></titleInfo><name type="personal"><namePart type="given">Etienne</namePart><namePart type="family">Hirsch</namePart><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ann M.</namePart><namePart type="family">Graybiel</namePart><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yves A.</namePart><namePart type="family">Agid</namePart><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="Letters to Nature"></genre><originInfo><publisher>Nature Publishing Group</publisher><dateIssued encoding="w3cdtf">1988-07-28</dateIssued><dateValid encoding="w3cdtf">1988-06-07</dateValid><copyrightDate encoding="w3cdtf">1988</copyrightDate></originInfo><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><relatedItem type="host"><titleInfo><title>Nature</title></titleInfo><identifier type="ISSN">0028-0836</identifier><part><date>1988</date><detail type="volume"><caption>vol.</caption><number>334</number></detail><detail type="issue"><caption>no.</caption><number>6180</number></detail><extent unit="pages"><start>345</start><end>348</end></extent></part></relatedItem><identifier type="istex">F760B501C9D54598B9FF7BD547A14192499296A9</identifier><identifier type="DOI">10.1038/334345a0</identifier><identifier type="ArticleID">334345a0</identifier><accessCondition type="use and reproduction" contentType="copyright">©1988 Nature Publishing Group</accessCondition><recordInfo><recordContentSource>NATURE</recordContentSource></recordInfo></mods></metadata><enrichments><istex:catWosTEI uri="https://api.istex.fr/document/F760B501C9D54598B9FF7BD547A14192499296A9/enrichments/catWos"><teiHeader><profileDesc><textClass><classCode scheme="WOS">MULTIDISCIPLINARY SCIENCES</classCode></textClass></profileDesc></teiHeader></istex:catWosTEI></enrichments><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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