Document text
Principal Investigator: CECILIA GIULIVI
Organization: UNIVERSITY OF CALIFORNIA AT DAVIS
Fiscal Year: 2022
Award: $439,250
Funding agency: National Institute of Neurological Disorders and Stroke
SUMMARY
Carriers of the FMR1 premutation have expanded CGG repeats at the 5’ UTR of this gene.
Carriers have a higher risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS),
a progressive neurodegenerative disease accompanied by tremor and ataxia as well as deficits
in cognition, learning, and other neuropsychological issues (depression, anxiety).
Neurodegeneration in FXTAS is accompanied by increased oxidative stress, lower
mitochondrial bioenergetic capacity, limited unfolded protein response and a poorly
characterized neuroinflammatory process. Surprisingly, not all carriers of the premutation
develop FXTAS and the progression from milder to more detrimental stages is highly variable
even in subjects with comparable age. As of today, there is no cure for FXTAS or to prevent its
development. Exosomes are proposed to mediate pathophysiological signaling in a variety of
target cells and their concentration spike in diseases associated with inflammation. Here, we
hypothesize that circulating exosomes with detrimental cargoes are contributors to the onset
and/or the progression of the disease. To this end, we will characterize exosomes from plasma
obtained from sex- and age-matched noncarriers, carriers with and without FXTAS. The
thorough characterization will entail evaluation of number and size, miRNA, and protein
profiling. The characterization will serve as a platform to identify qualitative and quantitative
differences as well as to identify the involvement of different biological pathways. The putative
“toxic” effect of exosomes derived from carriers with and without FXTAS will be assessed by
evaluating the bioenergetics of target cells (neurons and glia). These studies will provide an
insight on the mechanism underlying the impact of exosomal components to the onset of
mitochondrial dysfunction (as it is observed in carriers with FXTAS) and the progression of
ataxia and tremors, key features of FXTAS-affected subjects.
Terms: <5' Untranslated Regions><5'UTR><Affect><Age><Amyloidosis><Anxiety><Ataxia><Ataxy><Bioenergetics><Biological><Blood><Blood Plasma><Blood Reticuloendothelial System><Body Tissues><CD36><CD36 gene><CGG repeat><CGG repeat expansion><Caliber><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Signaling><Cell membrane><Cell-to-Cell Interaction><Cells><Clinical><Cognition><Coordination Impairment><Cytoplasmic Membrane><Data><Degenerative Neurologic Diseases><Degenerative Neurologic Disorders><Development><Diagnosis><Diameter><Disease><Disease Progression><Disorder><Dyssynergia><Energy Expenditure><Energy Metabolism><Escalante syndrome><Evaluation><FMR-1 Protein><FMR1><FMR1 Gene><FMR1 Premutation><FMR1 Protein><FMRP protein><FRAXA><FXTAS><Family><Fragile X><Fragile X Mental Retardation 1 Gene><Fragile X Mental Retardation Protein><Fragile X Syndrome><Fragile X premutation-associated tremor ataxia syndrome><Funding><GP3B><GP4><GPIV><Genes><Genotype><Glia><Glial Cells><Goals><Hortega cell><Immune response><Immunological response><Inflammation><Inflammatory Response><Intracellular Communication and Signaling><Kolliker's reticulum><Learning><Link><Location><Martin-Bell Syndrome><Martin-Bell-Renpenning syndrome><Matched Group><Mediating><Mediator><Mediator of Activation><Mediator of activation protein><Membrane><Mental Depression><Metabolic><Micro RNA><MicroRNAs><Microglia><Mitochondria><Molecular><Morbidity><Morbidity - disease rate><Morphology><NIH><Names><National Institutes of Health><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Degenerative Diseases><Nervous System Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neuroglia><Neuroglial Cells><Neurologic Degenerative Conditions><Neurologic Disorders><Neurological Disorders><Neuron Degeneration><Neurons><Neuropsychologies><Neuropsychology><Non-Polyadenylated RNA><Non-neuronal cell><Nonneuronal cell><Outcome><Oxidative Stress><Pathway interactions><Patients><Phenotype><Plasma><Plasma Membrane><Plasma Serum><Process><Proteins><Proteomics><PubMed><RNA><RNA Gene Products><Renpenning syndrome 2><Research><Research Subjects><Reticuloendothelial System, Serum, Plasma><Ribonucleic Acid><SCARB3><Signal Transduction><Signal Transduction Pathway><Signal Transduction Systems><Signaling><Testing><Tissues><Toxic effect><Toxicities><Tremor><United States National Institutes of Health><Vesicle><X-linked mental deficiency-megalotestes syndrome><X-linked mental retardation with fragile X syndrome><X-linked mental retardation-fragile site 1 syndrome><ages><amyloid disease><autism-fragile X (AFRAX) syndrome><autism-fragile X syndrome><base><biologic><biological signal transduction><cell type><cohort><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><depression><developmental><eligible participant><exosome><extracellular><extracellular vesicles><fra(X) syndrome><fra(X)(28) syndrome><fra(X)(q27) syndrome><fra(X)(q27-28) syndrome><fragile X FMR1 protein><fragile X associated tremor ataxia syndrome><fragile X mental retardation 1><fragile X mental retardation-1 protein><fragile X-associated tremor/ataxia syndrome><fragile X-mental retardation syndrome><fragile Xq syndrome><fragile site mental retardation 1><gene testing><gene-based testing><genetic testing><gitter cell><high risk><host response><immune system response><immunoresponse><insight><interest><mRNA Leader Sequences><macro-orchidism-marker X (MOMX) syndrome><macro-orchidism-marker X syndrome><mar(X) syndrome><marker X syndrome><membrane structure><mental retardation-macroorchidism syndrome><mesoglia><miRNA><miRNAs><microglial cell><microgliocyte><mitochondrial><mitochondrial dysfunction><nerve cell metabolism><nerve cement><nervous system disorder><neural degeneration><neurodegeneration><neurodegenerative><neurodegenerative illness><neuroinflammation><neuroinflammatory><neurological degeneration><neurological disease><neuron cell metabolism><neuron metabolism><neuronal><neuronal cell metabolism><neuronal degeneration><neuronal metabolism><neuropsychologic><novel><pathway><perivascular glial cell><plasmalemma><prevent><preventing><protein profiling><recruit><response><sex>