R01AG076745

Mechanisms of Mutant Prion Protein Aggregation within Endolysosomal Pathways

Ultrastructural studies of human patient brains with prion disease have revealed the accumulation of misfolded prion protein (PrP) within dystrophic neurites inside endolysosomes. Other complex structures co-exist within these dystrophies and are now considered common features of prion pathologies, including autophagic vacuole-like membrane-bound organelles, lysosomal electron-dense bodies, and enlarged endolysosomes. The mechanisms leading to the formation of these structures remain unknown.

Our studies have identified an endolysosomal pathway in mammalian neurons that we call Axonal Rapid Endosomal Sorting and Transport-dependent Aggregation (ARESTA), that drives the formation of neurotoxic axonal aggregates of a misfolded mutant PrP inside endo-membrane structures that we call "endoggresomes". The long-term goal of this proposal is to characterize the endocytic pathways that play a role in the pathophysiology of prion diseases, Alzheimer's disease, and Alzheimer's disease-related dementias, that will provide actionable targets for their pharmacological treatment.

The objectives of this proposal are:
(I) To determine the generality of the ARESTA pathway in the formation of endoggresomes in axons of neurons expressing various familial PrP mutations, and to characterize the molecular and ultrastructural architecture of neurotoxic endoggresomes;
(II) To determine the mechanisms of mutant PrP endoggresome-mediated axonal impairments; and
(III) To determine how the endolysosomal ARESTA pathway modulates the formation of axonal mutant PrP aggregates in vivo.

The central hypotheses are:
(I) ARESTA drives the formation of endoggresomes in various familial prion diseases by interactions with co-factors within endocytic routes;
(II) Mutant PrP endoggresome-induced pathologies act as axonotoxicity hubs that inhibit neuronal function by impairing local axonal cytoskeletal-organelle interactions; and
(III) Endolysosomal pathways modulate the formation and pathology of mutant PrP aggregates in vivo.

The proposed research is innovative because it provides a conceptual framework for developing models that include novel endolysosomal pathway-mediated mechanisms to explain how intra-axonal aggregates form and impair neuronal function in the prionopathies. The proposed research is significant because it identifies the endocytic pathway, specifically ARESTA and endoggresomes, as anti-aggregation targets for therapies to inhibit aggregate formation and reverse related pathologies. As amyloid-B peptides, tau, and most proteins that misfold in neurodegeneration transit within endocytic routes at some point in their processing routes, our findings are expected to be relevant to Alzheimer's disease and Alzheimer's disease-related dementias.

Scripps Research Institute

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]

La Jolla, California 920371000 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 361% from $726,467 to $3,350,798.