Journal
NEUROBIOLOGY OF DISEASE
Volume 153, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2021.105315
Keywords
Amyotrophic lateral sclerosis; Occludin; Ubiquitin; ITCH; Eps15
Categories
Funding
- National Natural Sciences Foundation of China [81872855, 82073835]
- CAMS Innovation Fund for Medical Sciences [2017-I2M-2-004]
- National Science and Technology Major Special Project on Major New Drug Innovation of China [2018ZX09711001-003-005, 2018ZX09711001-003-009]
- National Key R&D Program of China [2019YFC1708901]
- Fundamental Research Funds for the Central Universities [3332019070]
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The study reveals a novel mechanism of occludin degradation mediated by ALS-causing SOD1 mutants, showing that abnormal ROS induces occludin phosphorylation and ubiquitination leading to occludin degradation. Knockdown of either ITCH or Eps15 rescues occludin degradation, ameliorates endothelial barrier disruption.
It is increasingly recognized that blood-spinal cord barrier (BSCB) breakdown is a hallmark of amyotrophic lateral sclerosis (ALS). BSCB integrity is disrupted prior to disease onset. Occludin, as the functional component of the endothelial barrier, is downregulated in mouse models expressing ALS-linked superoxide dismutase-1 (SOD1) mutants. However, the molecular mechanisms underlying the regulation of occludin expression remain elusive. Here, using SOD1G93A transgenic mice and endothelial cells expressing SOD1 mutants of different biochemical characteristics, we found that the SOD1 mutation disrupted endothelial barrier integrity and that the occludin expression level was downregulated with disease progression. Our mechanistic studies revealed that abnormal reactive oxygen species (ROS) in mutant SOD1-expressing cells induced occludin phosphorylation, which facilitated the subsequent occludin ubiquitination mediated by the E3 ligase ITCH. Moreover, ubiquitinated occludin interacted with Eps15 to initiate its internalization, then trafficked to Rab5-positive vesicles and be degraded by proteasomes, resulting in a reduction in cell surface localization and total abundance. Notably, either ITCH or Eps15 knockdown was sufficient to rescue occludin degradation and ameliorate endothelial barrier disruption. In conclusion, our study reveals a novel mechanism of occludin degradation mediated by ALScausing SOD1 mutants and demonstrates a role for occludin in regulating BSCB integrity.
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