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Funded Studies

Understanding and Modeling the Complexity of Sporadic Parkinson's Disease: Genetic and Environmental Factors

Promising Outcomes of Original Grant:
As mutations in the glucocerebrosidase (GBA) gene are considered to be a risk factor for sporadic Parkinson's disease, we developed a mutant preclinical model with a selective disruption of the GBA gene in midbrain dopamine neurons. As far as one year of age, the majority of mutant models did not display any behavioral impairment or dopaminergic neurodegeneration. Only very few models demonstrated a clear and selective degeneration of the nigrostriatal pathway. Puzzling!
We received supplemental funding to answer the next obvious question: how to increase the number of affected models in order to develop a relevant and useful model of sporadic PD for testing novel neuroprotective therapies.
Objectives for Supplemental Investigation:
The main goal of the planned project is to mimic the complexity of sporadic PD, that is a multifactorial disorder. We propose to understand the role of GBA in the pathogenesis of sporadic PD, especially during aging, and how the genetic risk factor, GBA deficiency, interacts with environmental toxic exposures. First, as aging is the major risk factor for sporadic PD, we will follow the survival of midbrain dopamine neurons during the natural mouse aging (from 12 months of age until 24 months) in animals with a selective disruption of GBA in midbrain dopamine neurons. As sporadic PD is believed to be caused by the combination of both environmental and genetic factors, we will also combine this genetic factor (GBA deficiency) using these conditional KO animals with environmental factors (neurotoxins like pesticide, inhibitors of the proteasome, inhibitor of mitochondrial respiratory chain (MPTP) and inducer of inflammation) in order to elucidate the mechanism of the selective vulnerability of dopaminergic neurons in sporadic PD.
Importance of This Research for the Development of a New PD Therapy :
Although considerable progresses have been made in the pathogenesis of familial PD since the discovery of several mutated genes associated with familial PD, our knowledge about the etiology of the most common sporadic form is very limited. GBA mutations were consistently described to be a risk or susceptibility factor for developing PD. It is therefore crucial to understand how GBA mutations affect the survival of dopaminergic cells in sporadic PD. The goal of the proposed project is to clarify the role of GBA mutations in PD pathogenesis and develop relevant animal models that mimic the complexity of this multifactorial disorder. We believe that understanding the role of risk factors in PD pathogenesis will give important clues regarding what causes sporadic PD and will also lead to the discovery of novel therapeutic targets.

Final Outcome

The team has generated and characterized the GBA models. While no substantial phenotypes were reported, characterization is being continued to evaluate the models at later timepoints.


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