| Autor: |
Stephanie S, Sandoval-Pistorius, Julia E, Gerson, Nyjerus, Liggans, Jaimie H, Ryou, Kulin, Oak, Xingli, Li, Keyshla Y, Negron-Rios, Svetlana, Fischer, Henry, Barsh, Emily V, Crowley, Mary E, Skinner, Lisa M, Sharkey, Sami J, Barmada, Henry L, Paulson |
| Rok vydání: |
2022 |
| Zdroj: |
Scientific reports. 13(1) |
| ISSN: |
2045-2322 |
| Popis: |
The key protein implicated in Parkinson's disease and other synucleinopathies is α-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 α-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 α-synuclein is unknown. Using cellular and mouse models, we find that UBQLN2 decreases levels of α-synuclein, including the pS129 phosphorylated isoform. Pharmacological inhibition of the proteasome revealed that, while α-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 α-synuclein (A53T), native UBQLN2 becomes more insoluble. Collectively, our studies support a role for UBQLN2 in directly regulating pathological forms of α-synuclein and indicate that UBQLN2 dysregulation in disease may contribute to α-synuclein-mediated toxicity. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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