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Roles of UBE3A-mediated p18 regulation in synaptogenesis and synaptic plasticity

Award Number: R01NS104078
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2018
PERIOD OF PERFORMANCE END DATE: 02/29/2024

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Roles of UBE3A-mediated p18 regulation in synaptogenesis and synaptic plasticity - UBE3A, an E3 ligase in the ubiquitin-proteasomal system, plays important roles in brain development and function. Optimal CNS UBE3A expression is crucial since its deficiency results in Angelman syndrome (AS), while its over- expression increases the risk for autism. Yet, the precise function of UBE3A in the CNS remains largely unknown. In AS mouse models, Ube3a deficiency leads to deficits in motor function, learning and memory, and social interactions. We have recently reported that Ube3a deficiency leads to increased activation of mTORC1 but decreased activation of mTORC2, the two core complexes in the mechanistic target of rapamycin (mTOR) signaling pathway. However, how UBE3A deficiency results in mTORC1 over-activation remains unknown. Emerging evidence indicates that the presence of amino acids is essential for full mTORC1 activation. Amino acid-induced mTORC1 activation depends on the recruitment of mTORC1 to late endosomal/lysosomal membranes, a process involving the formation of heterodimers of a RagA or RagB, with a RagC or RagD through binding to the Ragulator. The anchoring of Ragulator to lysosomal membrane is through one of its components, p18. Myristoylation and palmitoylation in the N-terminal domain of p18 are critical for its lysosomal localization. Our preliminary results revealed that p18 levels were increased as a result of Ube3a deficiency in COS1 cells and in AS mouse brain. We further showed that p18 could be ubiquitinated by Ube3a in COS1 cells. These findings led us to propose the central hypothesis that, under normal conditions, lysosomal localized p18 levels are controlled by Ube3a-mediated ubiquitination, which targets p18 for proteasomal degradation. A correlate of this hypothesis is that lack of Ube3a-mediated p18 ubiquitination and degradation in AS mice results in imbalanced mTORC1/mTORC2 signaling and abnormal spine morphology and synaptic plasticity. We will first identify the ubiquitination sites in p18 and determine whether N-terminal acylation affects Ube3a- mediated p18 ubiquitination. We will then determine whether Ube3a-mediated p18 regulation plays important roles in synaptogenesis, synaptic plasticity, and experience-dependent remodeling of synapses using a multidisciplinary approach. Since both UBE3A deficiency and overexpression are linked to neurodevelopmental disorders, understanding UBE3A-mediated regulation of p18 and of mTOR signaling and its role in synaptogenesis and synaptic plasticity should shed light on basic neurobiological mechanisms, as well as on several neurological and neuropsychiatric diseases.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$17,979 )
2024	2022	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	6/24/2024	NON-COMPETING CONTINUATION	-$185
2024	2022	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/20/2024	NON-COMPETING CONTINUATION	-$17,794
														Subtotal = -$17,979

Issue Date FY: 2022 ( Subtotal = $308,438 )
2022	2022	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/24/2022	NON-COMPETING CONTINUATION	$277,594
2022	2022	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	3/24/2022	NON-COMPETING CONTINUATION	$30,844
														Subtotal = $308,438

Issue Date FY: 2021 ( Subtotal = $308,438 )
2021	2021	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/17/2021	NON-COMPETING CONTINUATION	$308,438
														Subtotal = $308,438

Issue Date FY: 2020 ( Subtotal = $308,438 )
2020	2020	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/17/2020	NON-COMPETING CONTINUATION	$308,438
														Subtotal = $308,438

Issue Date FY: 2019 ( Subtotal = $308,438 )
2019	2019	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/12/2019	NON-COMPETING CONTINUATION	$308,438
														Subtotal = $308,438

Issue Date FY: 2018 ( Subtotal = $308,438 )
2018	2018	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/5/2018	NEW	$308,438
														Subtotal = $308,438

Grand Total All Awards = $1,524,211

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Roles of UBE3A-mediated p18 regulation in synaptogenesis and synaptic plasticity

Award Number: R01NS104078

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/15/2018

PERIOD OF PERFORMANCE END DATE: 02/29/2024

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