| First Author | Kim T | Year | 2021 |
| Journal | J Cereb Blood Flow Metab | Volume | 41 |
| Issue | 5 | Pages | 1058-1066 |
| PubMed ID | 32703111 | Mgi Jnum | J:343053 |
| Mgi Id | MGI:7434767 | Doi | 10.1177/0271678X20943804 |
| Citation | Kim T, et al. (2021) Deletion of ubiquitin ligase Nedd4l exacerbates ischemic brain damage. J Cereb Blood Flow Metab 41(5):1058-1066 |
| abstractText | Ubiquitination by Nedd4 (neuronally expressed developmentally downregulated 4) family of HECT type E3 ligases plays a key role in degrading misfolded and damaged proteins, and its disruption leads to neurodegeneration. Parkinson's disease-causing protein alpha-Synuclein (alpha-Syn) is ubiquitinated by the Nedd4 family and degraded by endosomes. Nedd4l is the only Nedd4 homolog that showed upregulation in post-stroke surviving cortical neurons where it correlated with neuroprotection. We tested the role of Nedd4l after stroke by subjecting the Nedd4l(-/-) mice to transient middle cerebral artery occlusion. Focal ischemia significantly increased Nedd4l expression and poly-ubiquitinated alpha-Syn levels, and knockout of Nedd4l reduced post-ischemic poly-ubiquitinated alpha-Syn that is majorly located in the peri-infarct neurons. Co-immunoprecipitation further shows that focal ischemia enhances the alpha-Syn-Nedd4l interaction resulting in increased ubiquitination of alpha-Syn. Nedd4l knockout mice (n = 7 mice/group) showed exacerbated post-ischemic motor dysfunction manifested by decreased time on the rotarod and increased number of foot faults, and significantly increased ischemic brain damage. This suggests that Nedd4l might be a potential therapeutic target to minimize alpha-Syn-mediated toxicity after cerebral ischemia. |
