Structural Characterization of Human-Derived Induced Pluripotent Stem Cells for Application to Parkinson’s Disease

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In the case of Parkinson’s disease (PD), degeneration of key brain structures has been linked to the presence of abnormal alpha-synuclein protein, which is the current hallmark in aggregated cytoplasmic intraneuronal aggregates known as Lewy bodies (LBs) and Lewy neurites (LNs). Now that there is a clearer 3D picture of these aggregates based on electron microscopy data of postmortem human PD brain tissue acquired at C-CINA (Shahmoradian SH et al., in preparation), it is critical to identify and utilize a relevant cellular model.

Differentiated induced pluripotent stem cells (iPSCs) offer a comparable system that can be manipulated to show changes on shorter timescales than observed for the human brain. The goal is to perform ultrastructural analyses of the cells using primarily EM approaches such as correlative serial block face-scanning electron microscopy (SBF-SEM),  transmission electron microscopy (TEM) and electron tomography. These approaches will help to clarify the sub-cellular ultrastructural changes occurring during the differentiation of such iPSCs to dopaminergic neurons, allowing us to identify potential molecular mechanisms underlying aggregate growth in PD progression in the human brain.

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Lewy bodies occur in a large number of disorders including Alzheimer's disease, Downs syndrome and Picks disease. They are a classic hallmark of PD, where they are primarily found within neurons of the Substaitia Nigra.They only ocassionally ocurr extracellularly.

The generated iPSCs may provide insight into the pathogenesis of PD, and will potentially aid the the development of new drugs to treat the disease. At the moment, a Lewy body-like or protein aggregate model has not been described in either cell or animal models.

iPSCs are extremely challenging to grow and successfully differentiate, requiring special media, growth factors and extremely controlled environmental conditions. As a new human cell model, these cells need to be fully characterized, not only at the differentiated stage but also at the stem cell stage and at earlier developmental stages during the differentiation process.