Molecular Horizons Seminar - Professor Kensuke Ikenaka

α-Synuclein is an amyloidogenic protein linked to Parkinson’s disease (PD) and multiple system atrophy (MSA). Our team and others have developed techniques to amplify and analyze aggregates from patient brains, identifying disease-specific structural polymorphisms. However, the mechanisms behind these polymorphisms and their contribution to pathological diversity remain unclear. We identified phosphatidylinositol 3,4,5-trisphosphate (PIP3) as a key factor in the formation of α-synuclein polymorphisms, especially in PD, using multiple models including protein, cellular, and pathological studies1. Additionally, we showed that lysosomal membrane damage is crucial for cell-to-cell propagation of α-synuclein, with the extent of damage varying by polymorphism2. We are now investigating the molecular mechanisms regulating polymorph formation, finding that specific structures at the C-terminus of α-synuclein monomers, influenced by factors like salt, temperature, calcium, and PIP3, determine fibril structure. Lastly, we aim to understand the physiological relevance of α-synuclein’s ability to form amyloid fibrils, hypothesizing that it actively senses cellular environmental changes and adapts its structure accordingly.