| First Author | Sandoval-Pistorius SS | Year | 2023 |
| Journal | Sci Rep | Volume | 13 |
| Issue | 1 | Pages | 293 |
| PubMed ID | 36609661 | Mgi Jnum | J:334796 |
| Mgi Id | MGI:7427080 | Doi | 10.1038/s41598-022-26899-0 |
| Citation | Sandoval-Pistorius SS, et al. (2023) Ubiquilin-2 regulates pathological alpha-synuclein. Sci Rep 13(1):293 |
| abstractText | The key protein implicated in Parkinson's disease and other synucleinopathies is alpha-synuclein, and a post-translationally modified form of the protein, phosphorylated at serine 129 (pS129), is a principal component in Lewy bodies, a pathological hallmark of PD. While altered proteostasis has been implicated in the etiology of Parkinson's disease, we still have a limited understanding of how alpha-synuclein is regulated in the nervous system. The protein quality control protein Ubiquilin-2 (UBQLN2) is known to accumulate in synucleinopathies, but whether it directly regulates alpha-synuclein is unknown. Using cellular and mouse models, we find that UBQLN2 decreases levels of alpha-synuclein, including the pS129 phosphorylated isoform. Pharmacological inhibition of the proteasome revealed that, while alpha-synuclein may be cleared by parallel and redundant quality control pathways, UBQLN2 preferentially targets pS129 for proteasomal degradation. Moreover, in brain tissue from human PD and transgenic mice expressing pathogenic alpha-synuclein (A53T), native UBQLN2 becomes more insoluble. Collectively, our studies support a role for UBQLN2 in directly regulating pathological forms of alpha-synuclein and indicate that UBQLN2 dysregulation in disease may contribute to alpha-synuclein-mediated toxicity. |
