Adult neurogenesis in Parkinson's disease

Introduction and aim: Different acute and chronic experimental models mimick certain pathological hallmarks associated with Parkinson's disease (PD): while lesion models induce selectively a dopaminergic deficit in the nigrostriatal system, transgenic models lead to an accumulation of alpha-synuclein. In alpha-synuclein models wild-type alpha-synuclein accumulates during aging, whereas alpha-synuclein mutations (e.g. A53T) lead to an earlier onset as well as a more severe course of the disease. Accumulation of alpha-synuclein in the forebrain as well as in the olfactory bulb is particularly of clinical relevance, because olfactory dysfunction is one of the initial symptoms during the course of PD. More importantly, the olfactory bulb is one of the unique regions in the CNS characterized by a continuous generation of new neurons. Therefore, the aim of these consecutive studies was to analyze olfactory neurogenesis in different models of PD in the adult and during aging.

Methods and results: Applying the 6-OHDA lesion model 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. This result paralells findings in the olfactory bulb of PD patients where an increase of dopaminergic interneurons was detected. Both findings together imply that the decrease in smell of PD patients may be functionally related to an altered olfactory bulb neurogenesis. The combined infusion of growth factors (EGF, FGF-2) as well as the systemic application of D3 agonists are capable to compensate deficits of adult neurogenesis in PD models.

Adult neurogenesis is decreased in the subventricular zone – olfactory bulb system of overexpressing wild-type human alpha-synuclein transgenic mice due to a reduced survival of newly generated neurons. The decreased adult neurogenesis was even more pronounced in A53T mutant alpha-synuclein transgenic mice, and was mostly related to a reduction in cell proliferation within the subventricular zone. These findings mimick similar findings of reduced cell proliferation within the SVZ of PD patients.

Discussion: Both models – an acute dopaminergic lesion model as well as alpha-synuclein transgenic mice mimick important functional as well as cellular aspects of adult neurogenesis in PD patients. This implies that these models are ideal tools to test different strategies to enhance the endogenous pool of neural precursor- and stem cells in PD.