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Principal Investigator: Julie Kay Andersen
Organization: BUCK INSTITUTE FOR RESEARCH ON AGING
Fiscal Year: 2024
Award: $625,485
Funding agency: National Institute on Aging
PROJECT SUMMARY / ABSTRACT
Losses in protein homeostasis associated with accumulation of damaged, misfolded and aggregated proteins is
a characteristic feature of aging and many age-related neurodegenerative diseases. We hypothesize that this
may in part be driven by age-related dysfunctions in autophagy which establishes a prodromal process resulting
in decreased protein homeostasis and subsequent neurodegeneration. Growing evidence suggests that reduced
activity of transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis, could
underlie many neurodegenerative diseases. Based on these findings, we conducted a chemical screen in a
neuronal cell line for chemical compounds that induce TFEB. We identified a series of compounds that induce
TFEB and its targets to levels far exceeding that produced by the classic TFEB inducer rapamycin. Our lead
compound `C1' was tested across a wide range of proteotoxic disease models including in the nematode C.
elegans, in in vitro human neuronal tauopathy models, and in an in vivo mouse model of Parkinson's disease
(PD). In conjunction with elevations in autophagic flux, the compound was found to prevent the formation of
neurotoxic proteins aggregates and enhanced mitochondrial function. Subsequent genetic and biochemical
analysis shows that C1 induces TFEB by acting as a “reverse agonist” of the nuclear hormone receptor DAF-
12/FXR, validated via the use of known modulators of DAF-12/FXR. Although FXR is best known for its ability to
act in the liver and gut to maintain lipid homeostasis, it has recently been shown to be present in brain neurons
although its role in here is currently unexplored. Our results highlight a novel previously uncharacterized role for
FXR-TFEB signaling-mediated autophagy in age-associated neurodegenerative diseases. Based on these
results, we hypothesize that neuronal FXR mechanistically acts to modulate levels of TFEB-mediated autophagy
and as such constitutes a novel target for the treatment of age-related neurodegenerative diseases including
Alzheimer's disease (AD). To test this hypothesis, we propose to determine whether: (1) FXR inhibition results
in downstream TFEB signaling, triggering an increase in neuronal autophagy within neurons affected in AD and
(2) prevents subsequent development of established AD-related pathologies. Proposed studies include analyses
in both human iPSC-derived neurons and in brain tissues from an in vivo AD mouse model to interrogate features
associated with human disease including progressive development of mitochondrial deficits, Aβ and tau
neuropathology, losses in synapse integrity, and in mice, cognitive dysfunction.
Terms: <65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><AD dementia><AD model><AD related dementia><ADRD><Abscission><Affect><Aged 65 and Over><Aging><Agonist><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's and related dementias><Alzheimer's disease and related dementia><Alzheimer's disease and related disorders><Alzheimer's disease model><Alzheimer's disease or a related dementia><Alzheimer's disease or a related disorder><Alzheimer's disease or related dementia><Alzheimer's disease patient><Alzheimer's disease related dementia><Alzheimer's patient><Alzheimers Dementia><Amentia><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Autophagocytosis><Autoregulation><Aβ><Basal Transcription Factor><Basal transcription factor genes><Biochemical><Biogenesis><Brain><Brain Nervous System><Brain region><C elegans><C. elegans><C.elegans><Caenorhabditis elegans><Cell Communication and Signaling><Cell Line><Cell Signaling><CellLine><Characteristics><Chemicals><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Collaborations><Degenerative Neurologic Disorders><Dementia><Development><Disease><Disorder><Disturbance in cognition><Dysfunction><Encephalon><Excision><Extirpation><Functional disorder><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genetic><Genetic Transcription><Homeostasis><Human><Impaired cognition><In Vitro><Induced Neurons><Induced pluripotent stem cell derived human neuron><Intracellular Communication and Signaling><Lead><Lipids><Liver><Lysosomes><MT-bound tau><Mediating><Mice><Mice Mammals><Mitochondria><Modeling><Modern Man><Murine><Mus><Nematoda><Nematodes><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurofibrillary Tangles><Neurologic Degenerative Conditions><Neuron Degeneration><Neurons><Nuclear Hormone Receptor Superfamily><Nuclear Hormone Receptors><Origin of Life><Paralysis Agitans><Parkinson><Parkinson Disease><Pathologic><Pathology><Pb element><Physiological Homeostasis><Physiopathology><Primary Parkinsonism><Primary Senile Degenerative Dementia><Process><Proteins><RNA Expression><Rapamune><Rapamycin><Removal><Role><Series><Signal Transduction><Signal Transduction Systems><Signaling><Sirolimus><Strains Cell Lines><Surgical Removal><Synapses><Synaptic><Tauopathies><Testing><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><a beta peptide><abeta><above age 65><after age 65><age 65 and greater><age 65 and older><age 65 or older><age > 65><age associated><age associated neurodegeneration><age associated neurodegenerative disease><age associated neurodegenerative disorder><age correlated><age dependent><age dependent neurodegeneration><age dependent neurodegenerative condition><age dependent neurodegenerative disease><age dependent neurodegenerative disorder><age linked><age of 65 years onward><age related><age related neurodegeneration><age specific><age-driven neurodegenerative disorders><age-related neurodegenerative disease><age-related neurodegenerative disorder><aged 65 and greater><aged 65+><aged ≥65><aging associated neurodegeneration><aging associated neurodegenerative disease><aging related neurodegeneration><aging related neurodegenerative disease><aging related neurodegenerative disorder><alzheimer model><amyloid beta><amyloid-b protein><antagonism><antagonist><autophagy><beta amyloid fibril><biological signal transduction><brain tissue><cognitive dysfunction><cognitive loss><cultured cell line><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><developmental><disease model><disorder model><experiment><experimental research><experimental study><experiments><heavy metal Pb><heavy metal lead><hepatic body system><hepatic organ system><hiPSC-derived neurons><human disease><human iPSC-derived sensory neuron><human old age (65+)><iNeuron><iPSC-derived human neuron><in vivo><in vivo Model><insoluble aggregate><microtubule bound tau><microtubule-bound tau><mitochondrial><mouse model><murine model><neural degeneration><neurodegeneration><neurodegenerative><neurodegenerative illness><neurodegenerative phenotype><neurofibrillary degeneration><neurofibrillary lesion><neurofibrillary pathology><neurological degeneration><neuronal><neuronal degeneration><neuropathologic><neuropathologic tau><neuropathological><neuropathological tau><neuropathology><neuroprotection><neuroprotective><neurotoxic><novel><old age><over 65 years><pathophysiology><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><prevent><preventing><primary degenerative dementia><protein aggregate><protein aggregation><protein homeostasis><proteostasis><proteotoxic><proteotoxicity><resection><roundworm><senile dementia of the Alzheimer type><social role><soluble amyloid precursor protein><synapse><tangle><tau><tau Proteins><tau associated neurodegeneration><tau associated neurodegenerative process><tau factor><tau induced neurodegeneration><tau mediated neurodegeneration><tau neurodegenerative disease><tau neuropathology><tauopathic neurodegenerative disorder><tauopathy><therapeutic target><transcription factor><τ Proteins><≥65 years>