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Endoplasmic Reticulum Stress as a Novel Mechanism of Synaptic Dysfunction in Autism-Associated NLGN3 R451C Human Neurons

Award Number: F30MH108321
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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¿ DESCRIPTION (provided by applicant): Synaptic transmission controls information flow in the brain, and synaptic dysfunction is likely the biological basis of several neurodevelopmental disorders including autism spectrum disorders (ASDs), Rett syndrome, and neuropsychiatric disorders such as schizophrenia. Human genetic studies revealed that an increasing number of mutations in genes encoding synaptic adhesion proteins, such as the neuroligins (NLGNs), are linked to ASDs. Despite numerous animal studies, given the lack of a readily accessible source of primary neurons from subjects with autism, how mutations in these genes cause pathology and synaptic dysfunction in humans remains enigmatic. Using heterologous cell systems, we recently discovered that one autism-linked missense mutation, arginine (R) to cysteine (C) at position 451 of the human NLGN3 (NLGN3 R451C), disrupts protein trafficking and causes endoplasmic reticulum (ER) stress with activation of the Unfolded Protein Response (UPR), presenting a possible novel mechanism of autism etiology. This hypothesis has never been tested before in neurons and, more importantly, whether it translates to humans is not known. Fortunately, recently developed novel techniques in stem cell biology have made this analysis possible. Furthermore, it is now possible to create human neurons carrying gene mutations on an isogenic background, eliminating the genetic background "noise" that confounded previous stem cell research using samples from multiple individuals. Therefore, I propose to examine if ER stress and UPR are mechanistically linked with the synaptic dysfunction in human neurons carrying the R451C gene mutation on an isogenic background. I will investigate the sub-cellular localization of specific proteins involved in UPR and ER stress in parallel with putatively correlating pathways. An immediate and functional readout of neuronal phenotypes will be provided by morphometric and electrophysiological analyses. Mechanistic studies using small molecule chaperones and inhibitors of the UPR will solidify the potential link between ER stress, UPR and synaptic dysfunction. The most significant impact of this study is that it has the potential to 1) uncover a novel pathogenic mechanism by which a key autism-linked mutation causes neuronal dysfunction and 2) determine the roles of ER stress and the UPR in regulating synaptic transmission in a human neuronal context.


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: 2023 ( Subtotal = -$2,594 )
2023	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Mental Health Research Grants	000	4	11/23/2022	NON-COMPETING CONTINUATION	-$2,594
														Subtotal = -$2,594

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Mental Health Research Grants	000	4	4/23/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $50,016 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Mental Health Research Grants	000	4	6/20/2019	NON-COMPETING CONTINUATION	$50,016
														Subtotal = $50,016

Issue Date FY: 2018 ( Subtotal = $38,788 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Mental Health Research Grants	000	3	6/14/2018	NON-COMPETING CONTINUATION	$38,788
														Subtotal = $38,788

Issue Date FY: 2017 ( Subtotal = $38,308 )
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Mental Health Research Grants	000	2	5/31/2017	NON-COMPETING CONTINUATION	$37,840
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Mental Health Research Grants	001	2	7/25/2017	NON-COMPETING CONTINUATION	$468
														Subtotal = $38,308

Issue Date FY: 2016 ( Subtotal = $37,840 )
2016	2016	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Mental Health Research Grants	000	1	2/23/2016	NEW	$0
2016	2016	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Mental Health Research Grants	001	1	2/23/2016	NEW	$37,840
														Subtotal = $37,840

Grand Total All Awards = $162,358

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Endoplasmic Reticulum Stress as a Novel Mechanism of Synaptic Dysfunction in Autism-Associated NLGN3 R451C Human Neurons

Award Number: F30MH108321

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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