R01NS124802

Defining Mechanisms Underlying C9orf72-Associated Frontotemporal Dementia with C. elegans and Mammalian Models

Frontotemporal Dementia (FTD) is the second most common type of inherited dementia following Alzheimer's disease. FTD is caused by the progressive neurodegeneration of cells in the frontal and temporal lobe of the cerebral cortex. Expansion of a GGGGCC (G4C2) sequence in the first intron of the C9orf72 gene is the most common genetic cause of FTD and is responsible for approximately 25% of cases. However, the mechanisms by which expansion of the G4C2 sequence leads to neurodegeneration of specific neurons are not fully understood.

G4C2 RNA is transcribed in both sense and antisense directions, and both RNA strands can undergo an unusual type of translation called Repeat Associated Non-AG dependent Translation (RANT). RANT of the sense and antisense G4C2 RNA produces five distinct dipeptide repeat proteins (DPRs), two of which (PR and GR) confer strong toxicity in multiple model systems. To better understand the pathogenesis of C9orf72-mediated FTD, C. elegans models expressing pure DPRs were generated. It was found that both PR and GR were toxic in worms and caused neurodegeneration.

To define genes and pathways causing toxicity, an unbiased genetic suppressor screen was performed, and several highly conserved genes that blocked PR50 toxicity were discovered. One highly conserved suppressor is the nuclear E3 ligase adaptor SPOP. SPOP is widely studied in cancer since SPOP missense mutations are a major genetic cause of prostate and endometrial cancer. However, SPOP has never been linked to a neurodegenerative disease until now. The role of SPOP in DPR toxicity is conserved, as both SPOP genetic knockdown and an SPOP small molecule inhibitor block DPR toxicity in mammalian primary neurons.

One major SPOP target in cancer is BRD2/3/4, which are bromodomain-containing transcriptional regulatory proteins. It was found that inhibition of the BRD homolog BET-1 suppresses the ability of SPOP mutants to protect against DPR toxicity. Based on these findings, it is hypothesized that the SPOP pathway, currently being targeted for the treatment of cancer, may also underlie neurodegenerative pathology in C9 disease.

To test this hypothesis, the following objectives will be pursued:
1) Determine whether DPRs directly interact with SPOP to modulate known pathological pathways, such as defective nuclear transport and stress granule formation.
2) Delineate the mechanism by which SPOP, BRD, and possibly other substrates mediate DPR toxicity.
3) Determine if SPOP is a 'druggable' target for neuroprotection against DPRs in mammalian neurons.

These studies will interrogate a novel pathway associated with C9 disease using a diversity of approaches and experimental model systems. The discovery of this novel ubiquitination system could lead to new therapeutic insights for this incurable form of dementia.

Northwestern University

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (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. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND 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 of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

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

Chicago, Illinois 606114296 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 2858% from $122,321 to $3,618,812.