In:
eLife, eLife Sciences Publications, Ltd, Vol. 7 ( 2018-07-18)
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.
Type of Medium:
Online Resource
ISSN:
2050-084X
DOI:
10.7554/eLife.37993.001
DOI:
10.7554/eLife.37993.002
DOI:
10.7554/eLife.37993.004
DOI:
10.7554/eLife.37993.003
DOI:
10.7554/eLife.37993.005
DOI:
10.7554/eLife.37993.007
DOI:
10.7554/eLife.37993.006
DOI:
10.7554/eLife.37993.008
DOI:
10.7554/eLife.37993.010
DOI:
10.7554/eLife.37993.009
DOI:
10.7554/eLife.37993.011
DOI:
10.7554/eLife.37993.014
DOI:
10.7554/eLife.37993.012
DOI:
10.7554/eLife.37993.013
DOI:
10.7554/eLife.37993.015
DOI:
10.7554/eLife.37993.017
DOI:
10.7554/eLife.37993.016
DOI:
10.7554/eLife.37993.018
DOI:
10.7554/eLife.37993.021
DOI:
10.7554/eLife.37993.019
DOI:
10.7554/eLife.37993.020
DOI:
10.7554/eLife.37993.022
DOI:
10.7554/eLife.37993.023
DOI:
10.7554/eLife.37993.024
DOI:
10.7554/eLife.37993.026
DOI:
10.7554/eLife.37993.025
DOI:
10.7554/eLife.37993.027
DOI:
10.7554/eLife.37993.028
DOI:
10.7554/eLife.37993.030
DOI:
10.7554/eLife.37993.031
Language:
English
Publisher:
eLife Sciences Publications, Ltd
Publication Date:
2018
detail.hit.zdb_id:
2687154-3