iPSC Disease Modeling
Lewy body Formation: Modeling Parkinson's Disease Pathogenesis
In my initial experiments, I set out to see whether α-synuclein fibrils on their own could drive inclusion formation in human dopaminergic neurons, or whether an added stress signal was required. I treated neurons with fibrils alone and with fibrils followed by an immune challenge. Under the dual treatment, I observed the appearance of large, perinuclear inclusion bodies that were clearly distinct from the small puncta seen with fibrils alone.
Using electron microscopy, I could visualize these inclusions in detail—membrane-bound structures packed with fibrils, lysosomes, mitochondria, and filamentous material, closely resembling Lewy body–like inclusions.
α-Synuclein Tranposrt: Neuronal Transport of Aggregate Prone Proteins
In this set of experiments, I wanted to directly follow how neurons take up α-synuclein fibrils. I exposed human dopaminergic progenitors (left) and differentiated neurons (right) to fluorescently labeled fibrils and then tracked their localization over time. Within just a few minutes, the fibrils were already internalized and found inside lysosomes, marked by colocalization with LysoTracker and LAMP1. This rapid targeting to lysosomes was consistent across both progenitors and mature neurons. These results demonstrated that neurons rapidly engulf α-synuclein fibrils and direct them to the lysosomal system almost immediately after uptake.
