Funded Studies
This grant builds upon the research from a prior grant: The Role of Alpha-synuclein in the Pathogenesis of Parkinson's Disease in a Pre-clinical Model
Objective/Rationale:
Preliminary data from our laboratory demonstrated that the protein alpha synuclein (a-syn) might play a major role in an inherited autosomal recessive pre-clinical model for neurodegeneration. The main goal of this study is to investigate the genetic alteration of a-syn gene in this pre-clinical model for synucleinopathies, primarily Parkinson’s disease.
In parallel morphological, behavioral and neurochemical analyses will be performed to better understand the pathogenesis and disease progression.
Project Description:
Our proposed investigation of a-syn in the pathogenesis of PD in a pre-clinical model is predicated upon the observation of an unambiguous phenotype, with experimental evidence based on investigative pathology that supports a-syn as a priority candidate gene.
We proposed to investigate if there is a single gene alteration and if it is linked to a- syn by performing a pre-clinical model linkage analysis. Systematic phenotypic study including a-syn-induced pathology, counting the number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) and measurements of behavioral changes in the affected pre-clinical models compared to control littermate on a time point experiment. In addition, neurochemical analyses of dopamine and cytokines released by the glial cells in the brain of affected pre-clinical models will be assayed in a time point experiment.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The development of therapy for PD might evolve from a better understanding of pathogenesis of disease. Our inherited pre-clinical model provides a holistic approach to this disease, which is multifactorial in nature and unique in recapitulating the pathogenesis of human PD. Future in vitro and in vivo studies are needed to identify the factors that control cell-to-cell transfer of a-syn, and also the impact of genetic alterative changes in the pathogenesis of PD.
Anticipated Outcome:
Preliminary data require us to engage in a prioritized investigation of de novo mutations in a-syn within our pre-clinical model. We feel this is a solid first step towards unraveling the causal mutation(s) for the pre-clinical model of PD. Our proposed study is a highly focused investigation that will yield tangible results that either resolve the cause of our PD model in the pre-clinical model, or provide a natural and systematic segue to additional molecular genetic and/or whole-genome approaches.
Final Outcome
We made substantial progress for further characterization of our Berlin- Druckrey-IV pre-clinical model for better understanding of mechanism(s) in neurodegeneration. Genetic investigations brought us closer to identifying genetic mutations in pre-clinical models affected with movement disorder, phenotype resembling some aspects of Parkinson’s disease. Pathology and molecular biology studies performed on this model demonstrated significant accumulation of alpha-synuclein and neuronal degeneration in specific areas of the brain. Biochemical analysis showed a significant alteration of dopamine (DA) metabolism in brain striatum resulting in an increased of DOPAL, a metabolic product of DA, which is neurotoxic. In addition, there is a significant decline of the enzyme called ALDH1A2, which quickly breaks down DOPAL into a non-toxic chemical called DOPAC. It is believe that this alteration in DA metabolism is responsible for the phenotype that characterized this animal model as it is recently reported to occur in humans affected by PD. Further studies are necessary to complete the genetic investigation, and better understand the role of DOPAL accumulation in neurodegeneration. A better understanding of this “catecholadehyde hypothesis” can open new opportunity for therapeutic intervention in PD.