07-08-08(19:20:06)
Authors:
Winkler, Juergen
Institutions:
Section Molecular Neurology
University Erlangen
Germany
Title of abstract : Reduced neurogenesis in models of Parkinson disease
Abstract text:
Neurogenesis persists in the adult mammalian brain. One of the most exciting ideas for repair is that one might be able to harness the adult brain’s endogenous capacity for cell renewal. To stimulate adult neurogenesis, we choose a dopamine receptor agonist (DRA). These compunds have a potent effect to increase proliferation and olfactory bulb neurogenesis. Furthermore, we showed that the application of EGF and FGF-2 increases dopaminergic neurogenesis in the olfactory bulb, promote migration of newly-generated neuroblasts into the lesioned striatum, however fail to obtain a dopaminergic phenotype. Both studies indicate that exogenous applied compounds are capable to induce cellular repair mechanisms.
The second hypothesis was that neurogenic regions are more susceptible to protein aggregation disorders than other brain regions. We determined neurogenesis in transgenic mouse models for synucleinopathies: (1) In mice that expresses high levels of wild-type human -synuclein in neurogenic regions neuronal integration of progenitors is impaired. (2) A53T -synuclein transgenic mice showed a more pronounced decrease in olfactory neurogenesis. (3) Using a conditional tet-regulatable model of PD expressing human -synuclein we demonstrated, that that blocking synuclein expression restores adult neurogenesis and may offer new therapeutic targets. These findings suggest that pathways associated with -synuclein aggregation interfere with the generation and integration of newly generated neurons in neurogenic regions. Consecutively, we hypothesize that impaired neurogenesis in the olfactory bulb and the hippocampus may be the underlying structural substrate for pre-motor symptoms early in the course of PD such as olfactory deficits, depression and cognitive deficits.
