Fundamental Links Between Cellular Stress and Neurodegeneration in a Parkinson’s Disease Model

Parkinson’s disease (PD) is a neurodegenerative disorder that affects millions of individuals globally. The condition arises through the loss of dopaminergic neurons caused by various cellular stresses. In the surviving neurons of patients diagnosed with PD, there are presence of Lewy bodies comprised of aggregated proteins particularly α-synuclein. It is believed that the aggregated forms of α-synuclein induces cellular stress causing progressive cell death. However, it is not completely understood what stress pathways are activated by α-synuclein aggregates that results in PD-associated cellular death. This study aims to link α-synuclein oligomers and preformed fibrils (PFFs) to the integrated stress response (ISR) pathway. The ISR is involved in the reprogramming of cellular translation to determine the cell’s engagement in homeostatic or apoptotic downstream processes during various stress conditions including but not limited to oxidative and endoplasmic reticulum stress. We show that SH-SY5Y neuroblastoma cells will express ISR markers in response to toxic compounds such as sodium arsenite, thapsigargin and MPP+ iodide. Further, it was also demonstrated that oligomers and PFFs will activate the ISR which coincides with intracellular α-synuclein aggregation and oxidative stress. Additionally, this research aims to explore the manner in which small extracellular vesicles (sEVs) mediate pathological cell-to-cell transmission linked to PD. The data presented shows that upon cellular exposure to oligomers and PFFs, sEVs derived from these cells are positive for α-synuclein and various stress-associated proteins. Overall, the results show that α-synuclein aggregate-induced stress activates the ISR pathway and alters the proteome of sEVs.