Characterization and mobilization of adult neural stem cells to induce cellular regeneration in Parkinson’s disease

Parkinson’s disease is the most common observed progressive movement disorder and is observed in about 250 000 Germans (1% of the population over 55, the mean age of diagnosis). At present, the pharmacological therapy (levodopa substitution, dopamine agonists) enhances dopaminergic neurotransmission and is effective during the early course of the disease, however without halting the progressive death of the pigemented dopamine neurons of the substantia nigra pars compacta. Thus, in addition to the present pharmacological therapeutic strategies, a cell-based regenerative approach represents not only a very important and promising therapeutic alternative for PD patients. Cell replacement strategies can be divided into an exogenous and an endogenous mode. The exogenous strategy, for instance the transplantation of fetal brain cells into the striatum of PD patients, did not lead to a substantial clinical improvement. Alternatively, continuously dividing adult neural stem cells are physiologically present in regions of the adult brain and give rise to new neurons (neurogenesis). The stimulation of these endogenous stem and precursor populations is an attractive and promising mean for a cell- based therapy for PD patients. Neurogenic regions are observed in the dentate gyrus of the hippocampal formation and the subventricular zone (lining the lateral ventricles)/ olfactory bulb system. After establishing doublecortin (DCX) as a very powerful marker for newly generated neurons we are now able i.) to quantify non-invasively adult neurogensis and ii.) to test intervention aiming to enhance the generation of new neurons. PD is characterized by the loss of dopaminergic cells and impaired dopaminergic neurotransmission, leading to a specific impact on the genesis of endogenous neural stem cells in the adult brain. Our preliminary data indicate, that adult neurogenesis is severely altered in acute and transgenic models for PD (Winner et al., 2004 and 2006). The present proposal combines the use of DCX-based reporter mice and an acute neurochemical lesion model (induction of a dopaminergic deficit by applying 6-OHDA to the medial forebrain bundle) to be able to characterize the lesion specific modulation of adult neural stem cells. In particular, the proliferation, differentiation as well as the dopamine dependent modulation of newly generated cells will be examined. In addition, DCX-positive neuroblasts will be analyzed in specimen of PD patients with emphasis on the subventricular zone/ olfactory bulb system. This approach allows to characterize the neurogenic level in PD patients. In summary, the major goal of these studies focus on the generation of endogenous adult neural stem cells to induce regeneration in one of the most prevalent neurodegenerative diseases.


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