The Role of Alpha-Synuclein Aggregation in Endoplasmic Reticulum Protein Folding and Homeostasis


Protein homeostasis, or proteostasis, is essential for preserving all cellular functions and involves a balance of protein synthesis, folding, trafficking, and degradation. A collapse in proteostasis is a common feature of many neurodegenerative disorders that are characterized by the accumulation of insoluble protein aggregates in the brain. Parkinson’s disease (PD) is a neurodegenerative disorder characterized by large protein aggregates primarily composed of alpha-synuclein (a-synuclein), but how these aggregates perturb the proteostasis pathways is not well understood. To this end, we developed and characterized novel PD patient-derived midbrain dopaminergic neuron models that naturally accumulate and aggregate a-synuclein through endogenous SNCA triplications. It is well established that a-synuclein disrupts proper protein trafficking and lysosomal function. Here, we show that a-synuclein aggregates perturb the earlier stages of the proteostasis network by inducing dramatic fragmentation of the endoplasmic reticulum (ER) and compromising ER protein folding capacity. Subsequently, this leads to the misfolding and aggregation of immature lysosomal b-glucocerebrosidase (GCase) in the ER causing downstream lysosomal dysfunction. Despite these ER phenotypes, PD neurons fail to initiate the unfolded protein response, indicating that a-synuclein disrupts the ability of neurons to sense perturbations in ER protein folding. Importantly, these pathogenic phenotypes can be partially attenuated using rescue strategies that target the ER and enhance ER folding capacity. Specifically, we found that ER proteostasis enhancers promote soluble, functional GCase, while co-application with protein trafficking enhancers enhances lysosomal function and reduces pathological a-synuclein levels. Our studies suggest that protein aggregates perturb the ability of neurons to sense misfolding in the ER, and that synergistic enhancement of multiple branches of the proteostasis pathway may provide therapeutic benefit in PD and other synucleinopathies.

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