Deletion of ubiquitin ligase Nedd4l exacerbates ischemic brain damage.

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 α-Synuclein (α-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 α-Syn levels, and knockout of Nedd4l reduced post-ischemic poly-ubiquitinated α-Syn that is majorly located in the peri-infarct neurons. Co-immunoprecipitation further shows that focal ischemia enhances the α-Syn-Nedd4l interaction resulting in increased ubiquitination of α-Syn. Nedd4l knockout mice ( = 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 α-Syn-mediated toxicity after cerebral ischemia.