UBE3A-mediated p18/LAMTOR1 ubiquitination and degradation regulate mTORC1 activity and synaptic plasticity

Abstract

Accumulating evidence indicates that the lysosomal Ragulator complex is essential for full activation of the mechanistic target of rapamycin complex 1 (mTORC1). Abnormal mTORC1 activation has been implicated in several developmental neurological disorders, including Angelman syndrome (AS), which is caused by maternal deficiency of the ubiquitin E3 ligase UBE3A. Here we report that Ube3a regulates mTORC1 signaling by targeting p18, a subunit of the Ragulator. Ube3a ubiquinates p18, resulting in its proteasomal degradation, and Ube3a deficiency in the hippocampus of AS mice induces increased lysosomal localization of p18 and other members of the Ragulator-Rag complex, and increased mTORC1 activity. p18 knockdown in hippocampal CA1 neurons of AS mice reduces elevated mTORC1 activity and improves dendritic spine maturation, long-term potentiation (LTP), as well as learning performance. Our results indicate that Ube3a-mediated regulation of p18 and subsequent mTORC1 signaling is critical for typical synaptic plasticity, dendritic spine development, and learning and memory.

Angelman syndrome: a journey through the brain

“…The deficit of UBE3A in AS hippocampi leads to an increase in p18 and consequently enhanced mTORC1 activity. P18 knockdown results in decreased mTORC1 and ARC protein levels, leading to recovery of LTP, dendritic spine morphology, synaptic plasticity, and actin polymerization in cultured hippocampal neurons and to improved learning and memory in AS mice . All together, these results corroborate the hypothesis that the mTORC1/mTORC2 imbalance, increased ARC activity, and impairment of actin remodeling have a great impact on the buildup of AS pathology.…”

“…This model, also known as AS mice, presents ataxia, motor incoordination, inducible seizures, and sleep alterations, all of which are present in AS patients . Moreover, defects in context‐dependent learning and dendritic spine development deficits have been reported in these mice . Importantly, noticeable mouse strain‐dependent differences in AS phenotypes have been reported in this model that reminds us to be cautious when directly translating any mouse phenotype to human symptoms.…”

“…Recently, Sun et al . reported an increase in lysosomal localization of p18 (LAMTOR1) in the hippocampus of AS mice. p18 is a subunit of lysosomal Ragulator complex necessary for full activation of mTORC1.…”

“…mTOR is a kinase that serves as a core component of two distinct complexes [mammalian target of rapamycin complex (mTORC)1 and mTORC2] involved in autophagy, lysosome biogenesis, transcription, and actin dynamics, being considered a general integrator of signaling pathways crucial to healthy neuronal communication. In AS, deregulation of mTOR also has a major contribution to the pathogenesis . Sun and collaborators showed the increase in mTORC1 activity and in its S6K1 downstream target and the decrease in mTORC2 activity in hippocampal neurons of AS mice (Fig.…”

Characterizing spine issues: If offers novel therapeutics to Angelman syndrome

“…But the caveat is the severer mental retardation is not well reproduced in AS mice (Sonzogni et al., 2018) and the adult expressed Ube3a is not enough for the functional recovery on behaviors (Huang et al., 2012; Meng et al., 2015; Silva‐Santos et al, 2015). Since the success of rescuing neuronal electrophysiological properties (Rotaru, van Woerden, Wallaard, & Elgersma, 2018), synaptic plasticity like LTP, and learning and memory(Ciarlone, Grieco, D’Agostino, & Weeber, 2016; Ciarlone, Wang, Rogawski, & Weeber, 2017; Kaphzan et al., 2012; Sun et al., 2016, 2018; Sun, Zhu, et al, 2015; van Woerden et al., 2007), it is possible to develop interventions and treatments for AS.…”