Marxreiter, Franz and Nuber, Silke and Kandasamy, Mahesh and Klucken, Jochen and Aigner, Robert and Burgmayer, Ralf and Couillard-Despres, Sebastien and Riess, Olaf and Winkler, Jurgen and Winner, Beate (2009) Changes in adult olfactory bulb neurogenesis in mice expressing the A30P mutant form of alpha-synuclein. EUROPEAN JOURNAL OF NEUROSCIENCE, 29 (5). pp. 879-890. ISSN 0953-816X, 1460-9568
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | IDIOPATHIC PARKINSONS-DISEASE; DEPENDENT PROTEIN-KINASE; NEURAL STEM-CELLS; CHAIN MIGRATION; GENE-EXPRESSION; TRANSGENIC MICE; RAT-BRAIN; WILD-TYPE; LOCALIZATION; DEATH; adult neurogenesis; neural progenitor cells; Parkinson disease; subventricular zone; synucleinopathies |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Neurologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 22 Sep 2020 10:11 |
| Last Modified: | 22 Sep 2020 10:11 |
| URI: | https://pred.uni-regensburg.de/id/eprint/29347 |
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