Lentiviral vectors expressing chimeric NEDD4 ubiquitin ligases: An innovative approach for interfering with alpha-synuclein accumulation
| Autor: | Deran Erdengiz, Stefania Vogiatzis, Gloria Magro, Michele Celestino, Giorgio Palù, Claudia Del Vecchio, Cristina Parolin, Marta Trevisan, Arianna Calistri, Kathleen A. Maguire-Zeiss |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Alpha-synuclein
NEDD4 Parkinson’s disease Ubiquibodies Animals Cell Line Tumor Dopaminergic Neurons Genetic Vectors HEK293 Cells Humans Intracellular Space Lentivirus Mice Nedd4 Ubiquitin Protein Ligases Neural Stem Cells Parkinson Disease Recombinant Proteins Ubiquitination alpha-Synuclein QH301-705.5 ubiquibodies alpha-synuclein medicine.disease_cause Article Cell Line chemistry.chemical_compound Ubiquitin medicine Biology (General) chemistry.chemical_classification Mutation DNA ligase Tumor biology General Medicine Small molecule Neural stem cell Cell biology chemistry biology.protein Intracellular |
| Zdroj: | Cells, Vol 10, Iss 3256, p 3256 (2021) Cells; Volume 10; Issue 11; Pages: 3256 Cells |
| Popis: | One of the main pathological features of Parkinson’s disease (PD) is a diffuse accumulation of alpha-synuclein (aS) aggregates in neurons. The NEDD4 E3 Ub ligase promotes aS degradation by the endosomal–lysosomal route. Interestingly, NEDD4, as well as being a small molecule able to trigger its functions, is protective against human aS toxicity in evolutionary distant models. While pharmacological activation of E3 enzymes is not easy to achieve, their flexibility and the lack of “consensus” motifs for Ub-conjugation allow the development of engineered Ub-ligases, able to target proteins of interest. We developed lentiviral vectors, encoding well-characterized anti-human aS scFvs fused in frame to the NEDD4 catalytic domain (ubiquibodies), in order to target ubiquitinate aS. We demonstrate that, while all generated ubiquibodies bind to and ubiquitinate aS, the one directed against the non-amyloid component (NAC) of aS (Nac32HECT) affects aS’s intracellular levels. Furthermore, Nac32HECT expression partially rescues aS’s overexpression or mutation toxicity in neural stem cells. Overall, our data suggest that ubiquibodies, and Nac32HECT in particular, represent a valid platform for interfering with the effects of aS’s accumulation and aggregation in neurons. |
| Databáze: | OpenAIRE |
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