| First Author | Stojkovska I | Year | 2022 |
| Journal | Neuron | Volume | 110 |
| Issue | 3 | Pages | 436-451.e11 |
| PubMed ID | 34793693 | Mgi Jnum | J:324895 |
| Mgi Id | MGI:6877260 | Doi | 10.1016/j.neuron.2021.10.032 |
| Citation | Stojkovska I, et al. (2022) Rescue of alpha-synuclein aggregation in Parkinson's patient neurons by synergistic enhancement of ER proteostasis and protein trafficking. Neuron 110(3):436-451.e11 |
| abstractText | Neurodegenerative disorders are characterized by a collapse in proteostasis, as shown by the accumulation of insoluble protein aggregates in the brain. Proteostasis involves a balance of protein synthesis, folding, trafficking, and degradation, but how aggregates perturb these pathways is unknown. Using Parkinson's disease (PD) patient midbrain cultures, we find that aggregated alpha-synuclein induces endoplasmic reticulum (ER) fragmentation and compromises ER protein folding capacity, leading to misfolding and aggregation of immature lysosomal beta-glucocerebrosidase. Despite this, PD neurons fail to initiate the unfolded protein response, indicating perturbations in sensing or transducing protein misfolding signals in the ER. Small molecule enhancement of ER proteostasis machinery promotes beta-glucocerebrosidase solubility, while simultaneous enhancement of trafficking improves ER morphology, lysosomal function, and reduces alpha-synuclein. Our studies suggest that aggregated alpha-synuclein perturbs the ability of neurons to respond to misfolded proteins in the ER, and that synergistic enhancement of multiple proteostasis branches may provide therapeutic benefit in PD. |
