Changes in adult olfactory bulb neurogenesis in mice expressing the A30P mutant form of alpha‐synuclein
Identifieur interne : 000B44 ( Main/Exploration ); précédent : 000B43; suivant : 000B45Changes in adult olfactory bulb neurogenesis in mice expressing the A30P mutant form of alpha‐synuclein
Auteurs : Franz Marxreiter [Allemagne] ; Silke Nuber [Allemagne] ; Mahesh Kandasamy [Allemagne] ; Jochen Klucken [Allemagne] ; Robert Aigner [Allemagne] ; Ralf Burgmayer [Allemagne] ; Sebastien Couillard-Despres [Allemagne] ; Olaf Riess [Allemagne] ; Jürgen Winkler [États-Unis, Allemagne] ; Beate Winner [Allemagne]Source :
- European Journal of Neuroscience [ 0953-816X ] ; 2009-03.
English descriptors
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Abstract
In familial and sporadic forms of Parkinson’s disease (PD), alpha‐synuclein pathology is present in the brain stem nuclei and olfactory bulb (OB) long before Lewy bodies are detected in the substantia nigra. The OB is an active region of adult neurogenesis, where newly generated neurons physiologically integrate. While accumulation of wild‐type alpha‐synuclein is one of the pathogenic hallmarks of non‐genetic forms of PD, the A30P alpha‐synuclein mutation results in an earlier disease onset and a severe clinical phenotype. Here, we study the regulation of adult neurogenesis in the subventricular zone (SVZ)/OB system in a tetracycline‐suppressive (tet‐off) transgenic model of synucleinopathies, expressing human mutant A30P alpha‐synuclein under the control of the calcium/calmodulin‐dependent protein kinase II alpha (CaMK) promoter. In A30P transgenic mice alpha‐synuclein was abundant at the site of integration in the glomerular cell layer of the OB. Without changes in proliferation in the SVZ, significantly fewer newly generated neurons were observed in the OB granule cell and glomerular layers of A30P transgenic mice than in controls, most probably due to increased cell death. By tetracycline‐dependent abrogation of A30P alpha‐synuclein expression, OB neurogenesis and programmed cell death was restored to control levels. Our results indicate that, using A30P conditional (tet‐off) mice, A30P alpha‐synuclein has a negative impact on olfactory neurogenesis and suppression of A30P alpha‐synuclein enhances survival of newly generated neurons. This finding suggests that interfering with alpha‐synuclein pathology can rescue newly generated neurons, possibly leading to new targets for therapeutic interventions in synucleinopathies.
Url:
DOI: 10.1111/j.1460-9568.2009.06641.x
Affiliations:
- Allemagne, États-Unis
- Bade-Wurtemberg, Bavière, Californie, District de Moyenne-Franconie, District de Tübingen
- Erlangen, Tübingen
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The OB is an active region of adult neurogenesis, where newly generated neurons physiologically integrate. While accumulation of wild‐type alpha‐synuclein is one of the pathogenic hallmarks of non‐genetic forms of PD, the A30P alpha‐synuclein mutation results in an earlier disease onset and a severe clinical phenotype. Here, we study the regulation of adult neurogenesis in the subventricular zone (SVZ)/OB system in a tetracycline‐suppressive (tet‐off) transgenic model of synucleinopathies, expressing human mutant A30P alpha‐synuclein under the control of the calcium/calmodulin‐dependent protein kinase II alpha (CaMK) promoter. In A30P transgenic mice alpha‐synuclein was abundant at the site of integration in the glomerular cell layer of the OB. Without changes in proliferation in the SVZ, significantly fewer newly generated neurons were observed in the OB granule cell and glomerular layers of A30P transgenic mice than in controls, most probably due to increased cell death. By tetracycline‐dependent abrogation of A30P alpha‐synuclein expression, OB neurogenesis and programmed cell death was restored to control levels. Our results indicate that, using A30P conditional (tet‐off) mice, A30P alpha‐synuclein has a negative impact on olfactory neurogenesis and suppression of A30P alpha‐synuclein enhances survival of newly generated neurons. This finding suggests that interfering with alpha‐synuclein pathology can rescue newly generated neurons, possibly leading to new targets for therapeutic interventions in synucleinopathies.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>États-Unis</li></country><region><li>Bade-Wurtemberg</li><li>Bavière</li><li>Californie</li><li>District de Moyenne-Franconie</li><li>District de Tübingen</li></region><settlement><li>Erlangen</li><li>Tübingen</li></settlement></list><tree><country name="Allemagne"><noRegion><name sortKey="Marxreiter, Franz" sort="Marxreiter, Franz" uniqKey="Marxreiter F" first="Franz" last="Marxreiter">Franz Marxreiter</name></noRegion><name sortKey="Aigner, Robert" sort="Aigner, Robert" uniqKey="Aigner R" first="Robert" last="Aigner">Robert Aigner</name><name sortKey="Aigner, Robert" sort="Aigner, Robert" uniqKey="Aigner R" first="Robert" last="Aigner">Robert Aigner</name><name sortKey="Burgmayer, Ralf" sort="Burgmayer, Ralf" uniqKey="Burgmayer R" first="Ralf" last="Burgmayer">Ralf Burgmayer</name><name sortKey="Couillard Espres, Sebastien" sort="Couillard Espres, Sebastien" uniqKey="Couillard Espres S" first="Sebastien" last="Couillard-Despres">Sebastien Couillard-Despres</name><name sortKey="Kandasamy, Mahesh" sort="Kandasamy, Mahesh" uniqKey="Kandasamy M" first="Mahesh" last="Kandasamy">Mahesh Kandasamy</name><name sortKey="Klucken, Jochen" sort="Klucken, Jochen" uniqKey="Klucken J" first="Jochen" last="Klucken">Jochen Klucken</name><name sortKey="Klucken, Jochen" sort="Klucken, Jochen" uniqKey="Klucken J" first="Jochen" last="Klucken">Jochen Klucken</name><name sortKey="Nuber, Silke" sort="Nuber, Silke" uniqKey="Nuber S" first="Silke" last="Nuber">Silke Nuber</name><name sortKey="Riess, Olaf" sort="Riess, Olaf" uniqKey="Riess O" first="Olaf" last="Riess">Olaf Riess</name><name sortKey="Winkler, Jurgen" sort="Winkler, Jurgen" uniqKey="Winkler J" first="Jürgen" last="Winkler">Jürgen Winkler</name><name sortKey="Winner, Beate" sort="Winner, Beate" uniqKey="Winner B" first="Beate" last="Winner">Beate Winner</name></country><country name="États-Unis"><region name="Californie"><name sortKey="Winkler, Jurgen" sort="Winkler, Jurgen" uniqKey="Winkler J" first="Jürgen" last="Winkler">Jürgen Winkler</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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