R01AG078937

Elucidating the Roles of Transposable Elements in Alzheimer's and Related Dementias - Project Summary

AD is an age-related progressive neurodegenerative disorder affecting millions of Americans without effective interventions. The gradual accumulation of neurofibrillary tangles formed by abnormal protein aggregation, such as tau and amyloid-β (Aβ) protein, serves as the neuropathological hallmark of AD.

In recent years, the role of TAR DNA-binding protein 43 (TDP-43), a DNA and RNA-binding protein that has been heavily studied in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), has drawn increasing interest for AD pathogenesis. The pathological role of TDP-43 can be attributed to both its neurotoxicity in AD brain caused by its increased pathological aggregation in various brain regions such as the cortex, and its loss of normal function in the central nervous system. However, the detailed mechanistic role underlying TDP-43 mediated AD progression remains elusive.

One established biological role of TDP-43 is to regulate the expression of transposable elements (TEs), highly repetitive DNA sequences that occupy more than half of the human genome. A hallmark of TEs is that they harbor a three-stranded DNA:RNA hybrid structure referred to as R-loops, which have been linked to a wide variety of biological events, such as transcriptional regulation and genomic stability maintenance. Recent publications, along with our preliminary data, suggest a direct role of TDP-43 in regulating R-loop formation.

Our long-term goals are to elucidate the role of TDP-43, via R-loop regulation, for controlling TE expression in age-related neurodegeneration, and to translate our findings into clinically relevant strategies for the improved treatment of AD. In this application, we focus on how TDP-43 loss-of-function results in altered TE expression and leads to AD pathogenesis.

Our exciting preliminary data suggest:

1) Global alteration of TE expression and associated changes of the R-loop landscape are observed in human AD postmortem brains and are distinctive from AD mouse models.
2) Evolutionarily younger TEs show higher expression levels and stronger R-loop enrichment than more ancient TEs, in general, and they also harbor more drastic TE/R-loop changes in AD brains.
3) Stable depletion of TDP-43 in neuronal cells leads to aberrant R-loop alterations in TEs, concurrent with altered TE expression and 5-hydroxymethylcytosine (5hmC) profiling.
4) TDP-43 directly binds to a subset of TEs in neuronal cells which overlap with AD-associated TEs.
5) AD patient-derived 3D cortical organoids corroborate cellular and molecular phenotypes of AD, serving as an excellent human model system.

We will test the hypothesis that TDP-43 plays an important role in modulating TE expression via R-loop regulation, and TE dysregulation due to TDP-43 loss-of-function is critical for AD pathogenesis. Findings from these studies will provide unique mechanistic insights into the fundamental rules of TE expression regulation by TDP-43, which has the potential to discover new molecular targets with relevant clinical, translational, and therapeutic implications.

Emory University

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Atlanta, Georgia 303221047 United States

Single Zip Code

Elucidating the Roles of Transposable Elements in AD/ADRD and Aging (R01 Clinical Trial Not Allowed) (RFA-AG-22-021)

Amendment Since initial award the total obligations have increased 287% from $777,503 to $3,007,115.