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Cryptic exons and TDP-43 neurodegeneration in Alzheimer’s and multietiology dementias

Award Number: RF1NS120992
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: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Cryptic exons and TDP-43 neurodegeneration in Alzheimer’s and multietiology dementias - PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a devastating neurodegenerative disorder, often co-occurring with TDP-43 pathology, which is linked to accelerated cognitive decline. This research aims to fundamentally advance understanding of AD pathogenesis, specifically, addressing the critical role of TDP-43 pathology. This project will identify genetic determinants of TDP-43 pathology and its subtypes, associated molecular alterations, and the functional role of cryptic proteins in modulating AD pathogenesis and clinical outcomes. By leveraging our well-characterized postmortem cohort of 3,070 AD cases with comprehensive genetic, neuropathological, cognitive, neuroimaging, and transcriptomic data, this work will ultimately pave the way for more refined diagnostic tools and targeted therapeutic strategies for AD and its TDP-43-associated variants. In aim 1, we will determine genetic factors influencing TDP-43 pathology development and associated molecular changes by leveraging our recently generated genetic dataset (global screening array), with pathological measurements (TDP-43 dysfunction and subtype) from a large cohort of 3,070 postmortem cases with primary pathological diagnosis of AD. RNA sequencing from the amygdala -a TDP-43-relevant region- will be expanded and integrated to identify genetic variants associated with TDP-43 dysfunction and specific TDP-43 subtypes (α and β). In aim 2, we will define genetic factors contributing to cognitive decline and neuroimaging changes in AD by integrating genetic data with cognitive assessments and volumetric MRI neuroimaging. Importantly, this aim will also determine how differentially expressed genes and altered molecular pathways are associated with these cognitive and imaging measures within the context of TDP-43 pathology and cryptic proteins. Finally in aim 3, we will investigate the functional role of cryptic proteins in AD pathogenesis. Building on preliminary data, this aim will focus on the cryptic exon protein in HDGFL2 (HDGFL2 CE) to identify its novel interactors and delineate how the cryptic exon confers new, or modifies existing, functions to the HDGFL2 protein. This project offers a comprehensive investigation into the genetic determinants and molecular consequences of TDP-43 pathology, along with the functional relevance of cryptic proteins. This work is crucial for better understanding of AD heterogeneity and developing targeted diagnostic and therapeutic strategies for this devastating neurodegenerative 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 = $1,871,212 )
2026	2026	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	8/14/2026	COMPETING CONTINUATION	$1,871,212
														Subtotal = $1,871,212

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2021	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/21/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $2,374,752 )
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/25/2021	NEW	$2,374,752
														Subtotal = $2,374,752

Grand Total All Awards = $4,245,964

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Cryptic exons and TDP-43 neurodegeneration in Alzheimer’s and multietiology dementias

Award Number: RF1NS120992

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: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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