Fibrillar Alpha-Synuclein Alters the Intracellular Chaperone Levels within Hours of Its Internalization

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide. According to the Braak hypothesis, the disease spreads along specific neuroanatomical pathways. Studies indicate that fibrillar alpha-synuclein (F-αSyn) can propagate from cell-to-cell by following intercellular connections, leading to the selective death of certain cell groups like substantia nigra dopaminergic neurons and advancing the pathology. Internalized F-αSyn can be eliminated by lysosomes, proteasomes, or chaperones before it replicates inside the cell. Research has shown that F-αSyn can somehow escape from endosomes, lysosomes, and proteasomes and replicate itself. However, the impact of chaperones on intracellular levels during the initial hours of their internalization remains unknown. The present study investigates the effect of F-αSyn on chaperone levels within the first 6 and 12 h after internalization. Our findings showed that within the first 6 h, Hsc70 and Hsp90 levels were increased, while within 12 h, F-αSyn leads to a decrease or suppression of numerous intracellular chaperone levels. Exploring the pathological effects of PD on cells will contribute to identifying more targets for therapeutic interventions.