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Targeting the stress response in Angelman syndrome

Award Number: R01MH144153
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/06/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Targeting the stress response in Angelman syndrome - Abstract. Angelman syndrome is a severe neurodevelopmental disorder caused by the loss of maternal UBE3A, a neuronally imprinted gene that encodes the UBE3A ubiquitin ligase. The loss of UBE3A activity causes the dysregulation of an ensemble of proteins in neurons, but the identity of Angelman syndrome-relevant substrates and the pathways they affect remain poorly understood. The primary goal of the proposed research is to understand the neuronal pathways affected by the loss of UBE3A activity and to leverage this information for therapeutic design. Preliminary proteomics studies identified asparagine synthetase (ASNS) as a substrate of UBE3A. ASNS is best studied for its induced expression during the integrated stress response (ISR), an emerging pathway that is dysregulated in various neurodevelopmental disorders. Activation of the ISR suppresses protein synthesis in response to diverse stressors via phosphorylation of the α-subunit of eukaryotic translation initiation factor 2 (p-eIF2α). In human neurons and in brains of Angelman syndrome model mice that lack a copy of maternal Ube3a (Ube3am+/p+), ASNS protein levels are elevated. Moreover, Ube3am+/p+ animals exhibit altered global amino acid levels and increased p-eIF2α levels. Genetic correction of ASNS overabundance improved many behavioral phenotypes and microcephaly, the primary neuroanatomical deficit in Angelman syndrome. Based on these preliminary findings, this proposal aims to: 1) characterize the postnatal targeting of ASNS and ISR in a mouse model of Angelman syndrome, and 2) to characterize the role of ASNS in neuronal development. If successful, this work will provide important therapeutic targets for the treatment of Angelman syndrome and offer new insights for the role of ASNS and the ISR in neuronal development and disease.


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: 2026 ( Subtotal = $641,417 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research - Research Projects	000	1	8/10/2026	NEW	$641,417
														Subtotal = $641,417

Grand Total All Awards = $641,417

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Targeting the stress response in Angelman syndrome

Award Number: R01MH144153

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/06/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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