Mitochondrial endophenotypes of Parkinson's Disease
It is by now known that Parkinson's disease is not just a disease of the black substance and thus of the dopaminergic system in the brain, but it also relates to other brain structures and even peripheral systems such as the immune system and the regulation of our metabolism. In addition, the disease develops over decades until the first typical motor symptoms occur due to which the patient visits the patient, rendering the search for early diagnosis imperative. Therefore, in this project the mechanisms and molecular changes, which have been identified in other projects (in cell culture and in humans) as potentially characteristic of the Prakinson'sche disease (molecular signature of the disease), will be studied in the whole organism and over the whole lifespan until old age. For this purpose, in this project a humanized mouse model carrying the disease-causing mutation 126P in the Pink1 gene will be used. This mutation was chosen because this mutation elicits mitochondrial defects in cell culture. Specifically in this subproject the following tasks will be approached:
- 1) Systemic (= the whole organism) validation of the disease signatures identified in other subprojects in Pink1 mouse mutant, evtl. in a new mouse mutant (gene expression analysis, proteomeanalysis, behavioral and pathological analysis)
- 2.) Expansion and refinement of this disease signatures by analyzing young and old animals in order to determine the influence of the aging process.
- 3.) Determination of mitochondrial defect in diverse - not only neuronal - cell types
- 4) validation of the treatment with test substances (analog to subproject 6 ) in the mutant mice and determining the resultant change in molecular signature.
Specifically, the analysis of specific proteomic markers at various times of disease development in easily accessible body fluids would significantly improve the diagnosis of this disease, and might open the possibility for defining new preventive measures – based on the newly identified alterations in molecular signatures.