Cylindromatosis drives synapse pruning and weakening by promoting macroautophagy through Akt-mTOR signaling.

Abstract

The lysine-63 deubiquitinase cylindromatosis (CYLD) is long recognized as a tumor suppressor in immunity and inflammation, and its loss-of-function mutations lead to familial cylindromatosis. However, recent studies reveal that CYLD is enriched in mammalian brain postsynaptic densities, and a gain-of-function mutation causes frontotemporal dementia (FTD), suggesting critical roles at excitatory synapses. Here we report that CYLD drives synapse elimination and weakening by acting on the Akt-mTOR-autophagy axis. Mice lacking CYLD display abnormal sociability, anxiety- and depression-like behaviors, and cognitive inflexibility. These behavioral impairments are accompanied by excessive synapse numbers, increased postsynaptic efficacy, augmented synaptic summation, and impaired NMDA receptor-dependent hippocampal long-term depression (LTD). Exogenous expression of CYLD results in removal of established dendritic spines from mature neurons in a deubiquitinase activity-dependent manner. In search of underlying molecular mechanisms, we find that CYLD knockout mice display marked overactivation of Akt and mTOR and reduced autophagic flux, and conversely, CYLD overexpression potently suppresses Akt and mTOR activity and promotes autophagy. Consequently, abrogating the Akt-mTOR-autophagy signaling pathway abolishes CYLD-induced spine loss, whereas enhancing autophagy in vivo by the mTOR inhibitor rapamycin rescues the synaptic pruning and LTD deficits in mutant mice. Our findings establish CYLD, via Akt-mTOR signaling, as a synaptic autophagy activator that exerts critical modulations on synapse maintenance, function, and plasticity.

• Authors: Alexis S Zajicek, Hongyu Ruan, Huihui Dai, Mary C Skolfield, Hannah L Phillips, Wendi J Burnette, Behnam Javidfar, Shao-Cong Sun, Schahram Akbarian, Wei-Dong Yao
• Journal: Molecular psychiatry (Mol Psychiatry) Vol. 27 Issue 5 Pg. 2414-2424 (05 2022) ISSN: 1476-5578 [Electronic] England
• PMID: 35449295 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Deubiquitinating Enzymes

Topics

• Animals
• Deubiquitinating Enzymes (metabolism)
• Macroautophagy
• Mammals (metabolism)
• Mice
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (physiology)
• Synapses (metabolism)
• TOR Serine-Threonine Kinases (metabolism)