R01AG074609

Evaluation of a Novel NLK Function in Lysosome Biogenesis and Neurodegenerative Diseases - 1R01AG074609-01

Janghoo Lim

In the majority of neurodegenerative diseases, including Alzheimer's disease (AD), one or more proteins aggregate over the course of disease progression. In the case of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), AD, and other AD-related dementias (ADRDS), cytoplasmic inclusions of transactive response DNA binding protein 43 kDa (TDP-43) are observed in a large percentage of patients with sporadic and familial forms of disease. This aberrant accumulation of cytoplasmic TDP-43 is thought to underlie gain of toxic functions and exacerbate loss of nuclear function pathogenic mechanisms; therefore, preventing the formation or promoting the clearance of these inclusions may be an effective therapeutic approach for TDP-43 proteinopathies, such as AD and ADRDS. Currently, there are no therapeutics that effectively alter the course of most neurodegenerative diseases associated with TDP-43 proteinopathy.

We have recently identified Nemo-like kinase (NLK) as a negative regulator of the lysosome, a key organelle involved in cellular protein quality control that is capable of clearing toxic aggregated proteins. This proposal aims to better understand the basic molecular mechanism of NLK's regulation of lysosome gene expression in the nervous system and to test the modulatory effects of NLK in ADRD animal models of TDP-43 aggregation. We propose the following three specific aims.

Aim 1 will employ unbiased and targeted approaches to uncover fundamental mechanistic insights into the regulation of lysosome gene expression by NLK in neurons.

Aim 2 will determine which cell types mediate the function of NLK in the regulation of the lysosome and TDP-43 proteinopathy in the nervous system in vivo using wild-type and TDP-43 animal models.

Aim 3 will expand the scope of the proposed study to understand the therapeutic implications of NLK reduction in animal models of TDP-43 aggregation through genetic and pharmacological reduction of NLK levels at varying times in adulthood in vivo. In doing so, we will test the effect of NLK reduction in the control of the onset and progression of pathological and motor behavioral changes in TDP-43 mouse models of ADRD. Aims 2 and 3 will provide critical proof-of-principle evidence regarding the effectiveness of lysosomal modulation in pre-clinical models of protein aggregation disorders.

Together, this project will reveal novel molecules involved in lysosomal regulation in neurons that may be potential targets in the treatment of various neurodegenerative diseases, including AD and several AD-related disorders.

Yale Univ

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]

New Haven, Connecticut 065103206 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 398% from $808,198 to $4,024,826.