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The Roles of the Neurodevelopmental Disease-linked Ube3a Protein in Golgi Satellite Function

Award Number: R21MH134184
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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The Roles of the Neurodevelopmental Disease-linked Ube3a Protein in Golgi Satellite Function - Project summary The clinical manifestations of autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDDs) are thought to be caused by an imbalance of excitatory and inhibitory neuronal activity. We have discovered that changes in activity cause long-term changes in the intracellular architecture of neurons. The long-term changes occur through the formation of novel organelles, called Golgi satellites (GSats), that have many of the functions of the Golgi apparatus (GA) in the soma. Preliminary data demonstrate that activity changes cause GSats to position at synapses, particularly in dendrites at spine heads. Preliminary data also show that the ASD- and NDD-related protein Ube3a localizes to GSats, and that this association is increased in response to neuronal stimulation. At dendritic synaptic sites, GSats are the “missing” organelles needed for proper glycosylation of locally translated membrane and secreted proteins important for synaptic plasticity. GSat formation transforms local secretory pathways at postsynaptic sites so that locally translated membrane and secreted proteins are properly glycosylated. In addition, multiple glycoproteins which are both associated with ASD and involved in synaptic function are endocytosed into early endosomes and then trafficked into GSats where glycans can again be processed. Through these functions, GSats can remodel the neuronal surface glycoproteome and mediate rapid changes in the sialic acid content of synaptic glycoproteins. These processes can lead to changes in protein function which can then contribute to the altered synaptic function observed in ASD and NDDs. In this proposal we will examine how GSats interact with the products of the ASD- and NDD-risk gene UBE3A. The association of Ube3a with GSats is hypothesized to regulate GSat acidification, which in turn influences the activity of resident sialyltransfereases and their ability to remodel the neuronal surface glycoproteome and rapidly alter synaptic protein sialic contents. We will determine how changes in Ube3a expression alters sialic acid content at synapses and on a set of synaptic and ASD-related glycoproteins. We will also characterize how changes in Ube3a expression regulate activity-induced modulation of GSat formation and localization in relative to synapse, how these changes correlate with synaptic plasticity. We have developed a series of techniques, assays and preparations that will allow us to perform these experiments in both primary neuronal cultures and in ex vivo mouse hippocampal preparations.


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 = $0 )
2026	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Mental Health Research Grants	000	2	1/6/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $204,278 )
2025	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Mental Health Research Grants	000	2	2/13/2025	NON-COMPETING CONTINUATION	$173,636
2025	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Mental Health Research Grants	001	2	9/22/2025	NON-COMPETING CONTINUATION	$30,642
														Subtotal = $204,278

Issue Date FY: 2024 ( Subtotal = $261,278 )
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Mental Health Research Grants	000	1	1/26/2024	NEW	$261,278
														Subtotal = $261,278

Grand Total All Awards = $465,556

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The Roles of the Neurodevelopmental Disease-linked Ube3a Protein in Golgi Satellite Function

Award Number: R21MH134184

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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