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Localized translational dysregulation in an autism spectrum disorder model using in situ cryo-EM

Award Number: R21NS137060
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: 07/01/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Localized translational dysregulation in an autism spectrum disorder model using in situ cryo-EM - ABSTRACT/PROJECT SUMMARY We propose to leverage innovative in situ cryo-electron microscopy (cryo-EM) techniques to study dysregulated protein synthesis, termed translation, in an autism spectrum disorder (ASD) model. Dysregulated translation disrupts normal neuronal plasticity, leading to various disorders including autism spectrum disorder (ASD), major depressive disorders, chronic pain, and other pathologies affecting millions worldwide. However, a comprehensive understanding of location-dependent ribosome regulation, which plays a crucial role in plasticity, remains elusive. Current methods to study single events at a high resolution in cells are limited, hindering the acquisition of this essential knowledge. We will overcome this limitation using correlative fluorescence microscopy and in situ cryo-EM. The loss of the Fragile-X mental retardation 1 (FMR1) gene product, known as FMRP, is responsible for the most prevalent form of heritable ASD. FMRP interacts with polysomes within two types of RNA granules: fragile X granules (FXGs) and neuronal RNA granules (nRNAgs), also known as transport granules. Excessive translation resulting from the absence of FMRP has been associated with long-term memory impairment, supported by the notion that neuronal granules contribute to memory and synaptic plasticity. Despite its broad importance in neuronal function, the pleiotropic nature of FMRP has prevented the field from developing a unified understanding of its functions and its underlying role in local translation. To address this, we will develop novel high-resolution approaches to unravel the functions of FMRP in translation within neuronal models. These advances will pave the way for investigating FMRP's involvement in translational regulation using disease models derived from human induced pluripotent stem cells (iPSCs). We propose in this project to apply cutting-edge cryo-EM methods and develop effective workflows in two Specific Aims: In Aim 1, we will develop a protocol to determine the localization, activity, and structure of FMRP granule-associated ribosomes in iPSCs. This aim will establish a workflow and reveal how ribosome localization and activity are regulated by FMRP in neurites. In aim 2, we will determine the localization, activity and structures of ribosomes associated with nRNAgs and FXGs. This aim will reveal how ribosome inactivation differs between granule types. More broadly, these investigations will lay the foundation for mechanistic studies aimed at understanding how translation contributes to human disease in a location-specific manner. Our work will provide structural insights into translational regulation, a fundamental process for proper neuron function. Furthermore, it will enable the application of this analysis to patient-derived human iPSC models of neurodevelopmental diseases, aligning with the missions of the National Institute of Neurological Disorders and Stroke.


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	2024	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/21/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $443,121 )
2024	2024	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/26/2024	NEW	$443,121
														Subtotal = $443,121

Grand Total All Awards = $443,121

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Localized translational dysregulation in an autism spectrum disorder model using in situ cryo-EM

Award Number: R21NS137060

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: 07/01/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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