Study Rationale: Transgenic small models have been used as gold standard to study human brain diseases, but it is unclear how conclusive and faithfully these models reflect pathophysiological conditions in human-diseased brain cells. Examining disease processes in patient brain cells should allow us to identify cellular dysfunctions that lead to neurodegeneration in Parkinson’s disease (PD). As patient brain cells are only accessible post-mortem when late-stage cellular dysfunction and adaptive processes are at play, we will employ brain cells generated from patient-induced pluripotent stem cells (iPSCs) to understand early cellular dysfunctions and identify targets to devise novel therapeutic strategies.
Hypothesis: We hypothesize that iPSCs from well-defined familial forms of PD can be used as initial templates to further study cellular dysfunctions in idiopathic PD, and to examine the specificity of the pathways that dictate onset and progression.
Study Design:We propose to uncover cellular dysfunctions by analyzing changes in the proteome of brain cells generated from iPSCs of PD patients compared to healthy controls. We will at first generate iPSC-derived midbrain minibrains containing dopaminergic neurons, astrocytes and oligodendrocytes from the iPSCs PPMI cohort. Next, we will determine the proteomic profiles, including post-translational modifications of these cell types using mass spectrometry-based quantitative proteomic analyses. Finally, we will perform in-depth statistical and bioinformatics analyses on the protein profiles to establish a list of dysregulated proteins and to identify cellular pathway and network alterations in diseased brain cells. The molecular targets will be confirmed using dedicated functional assays, based on the alterations identified.
Impact on Diagnosis/Treatment of Parkinson’s disease: The findings will allow us to: 1) establish disease-specific signatures, 2) identify prognostic biomarkers, 3) develop a stratification strategy for precision medicine, and 4) identify novel targets for therapeutic intervention.
Next Steps for Development: Through the project, we will develop robust patient-based models to test treatments or develop them.