The K63 deubiquitinase CYLD modulates autism-like behaviors and hippocampal plasticity by regulating autophagy and mTOR signaling.
Elisa ColomboGuilherme HortaMona K RoeslerNatascha IhbeStuti ChhabraKonstantin RadyushkinGiovanni Di LibertoMario KreutzfeldtSven SchumannJakob von EngelhardtDoron MerklerChristian BehlThomas MittmannAlbrecht M ClementEsther Von StebutMichael J SchmeisserPublished in: Proceedings of the National Academy of Sciences of the United States of America (2021)
Nondegradative ubiquitin chains attached to specific targets via Lysine 63 (K63) residues have emerged to play a fundamental role in synaptic function. The K63-specific deubiquitinase CYLD has been widely studied in immune cells and lately also in neurons. To better understand if CYLD plays a role in brain and synapse homeostasis, we analyzed the behavioral profile of CYLD-deficient mice. We found that the loss of CYLD results in major autism-like phenotypes including impaired social communication, increased repetitive behavior, and cognitive dysfunction. Furthermore, the absence of CYLD leads to a reduction in hippocampal network excitability, long-term potentiation, and pyramidal neuron spine numbers. By providing evidence that CYLD can modulate mechanistic target of rapamycin (mTOR) signaling and autophagy at the synapse, we propose that synaptic K63-linked ubiquitination processes could be fundamental in understanding the pathomechanisms underlying autism spectrum disorder.
Keyphrases
- autism spectrum disorder
- intellectual disability
- cell death
- endoplasmic reticulum stress
- healthcare
- signaling pathway
- oxidative stress
- cerebral ischemia
- mental health
- cell proliferation
- attention deficit hyperactivity disorder
- multiple sclerosis
- blood brain barrier
- brain injury
- subarachnoid hemorrhage
- resting state