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RESEARCH PRODUCT
The K63 deubiquitinase CYLD modulates autism-like behaviors and hippocampal plasticity by regulating autophagy and mTOR signaling.
Stuti ChhabraGuilherme HortaDoron MerklerKonstantin RadyushkinMona K. RoeslerElisa ColomboGiovanni Di LibertoAlbrecht M. ClementSven SchumannChristian BehlJakob Von EngelhardtMario KreutzfeldtThomas MittmannMichael J. SchmeisserNatascha IhbeAri Waismansubject
MaleAutism Spectrum DisorderNerve Tissue ProteinsHippocampal formationHippocampusDeubiquitinating enzymeSynapseMiceUbiquitinAutophagyAnimalsAutistic DisorderMechanistic target of rapamycinPI3K/AKT/mTOR pathwayNeuronsMultidisciplinarybiologyUbiquitinLysineTOR Serine-Threonine KinasesAutophagyMicrofilament ProteinsUbiquitinationLong-term potentiationBiological SciencesDeubiquitinating Enzyme CYLDMice Inbred C57BLSynapsesbiology.proteinFemaleNeuroscienceSignal Transductiondescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2021-09-21 | Proceedings of the National Academy of Sciences of the United States of America |