Förderprojekte

Förderbeginn 01.07.2001

Adulte neurale Stammzellen im peripheren Nervensystem

Prof. Dr. Jürgen Winkler
Universität Regensburg
Klinik und Poliklinik für Neurologie - Kliniknahe Grundlagenforschung

Prof. Dr. Beate Winner
Universität Regensburg
Klinik und Poliklinik für Neurologie - Kliniknahe Grundlagenforschung

Prof. Dr. Leon Thal
University of California, San Diego
Department of Neurosciences

Dr. D. Pizzo
University of California, San Diego
Department of Neurosciences

Die Existenz adulter neuraler Stammzellen (aNSC) wurde im Zentralnervensystem für verschiedene Säuger - Nagetiere, Primaten und Menschen - in zwei neurogenen Zonen, dem Hippocampus und der subventrikulären Zone, nachgewiesen. Ziel dieses Projektes ist es zu untersuchen, inwieweit auch aNSC im peripheren Nervensystem (PNS) existieren. Mit den im Labor von Dr. Winkler etablierten Markierungsmethoden soll zusätzlich das Proliferations-, Migrations- und Differenzierungsverhalten von aNSC im PNS charakterisiert werden. In Zusammenarbeit mit Prof. Thal und Dr. Pizzo soll durch die intrazerebroventrikuläre Injektion von Wachstumsfaktoren untersucht werden, ob das Proliferations- und Differenzierungsverhalten der aNSC des PNS modulierbar ist. Dieser Experimente dienen dazu, die aNSC assoziierte regenerative Kapazität des PNS zu charakterisieren, mit dem Ziel dieses Potential bei Erkrankungen des PNS zu nutzen.

Abschlussbericht
Impaired adult neurogenesis: potential mechanisms involved in olfactory impairment in PD

Our objective was to delineate mechanism of olfactory bulb dysfunction in Parkinson disease (PD).

Olfactory impairment is occuring early in PD. Morphologically, alpha-synuclein aggregation is found first in the olfactory bulb in PD and has been attributed to the functional impairment. The olfactory bulb is of special interest for studying neurogenesis in the adult brain, as newly generated dopaminergic and gabaergic interneurons continously integrate into this structure.

Adult neurogenesis was studied in the olfactory bulb system in 2 different PD animal models: 6-Hydroxydopamine (6-OHDA) lesioned rats and human wildtype alpha synuclein overexpressing mice. We present two mechanisms of impaired adult olfactory neurogenesis:

(1) In an animal model of synucleinopathies, the human wild-type overexpressing alpha synuclein mice under a PDGF-promotor, we delineate decreased survival of newly generated cells due to increased cell death at the stage of integration into olfactory bulb circuitries. Moreover we show, that this effect is present in young and old animals.

(2) In a second approach we study the impact on olfactory neurogenesis after 6-OHDA lesions to the medial forebrain bundle. Proliferation of neural precursor cells is decreased significantly after dopaminergic deafferentation. 6-OHDA lesions induced opposite effects in different regions of the olfactory bulb: a transient decrease in the granule cell layer contrasts to a sustained increase of newly generated neurons in the glomerular layer. These data point towards a shift in the ratio of newly generated interneurons in the olfactory bulb layers. Thus, loss of dopaminergic input to the SVZ led to a distinct cell fate decision towards stimulation of dopaminergic neurogenesis in the olfactory bulb glomerular layer.

Conclusion:
These studies support the accumulating evidence, that besides neuronal degeneration altered adult neurogenesis may play a crucial role in olfactory dysfunction in PD.