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Principal Investigator: Kyunghee Koh
Organization: THOMAS JEFFERSON UNIVERSITY
Fiscal Year: 2024
Award: $234,000
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY
Frontotemporal dementia (FTD) is a neurodegenerative disease that belongs to a group of Alzheimer’s
disease and related dementias (AD/ADRD) and is one of the most common dementias for people under 60.
Our internal circadian clock controls numerous critical biological processes, including sleep-wake cycles.
Circadian and sleep disruptions are prevalent among patients with neurodegenerative diseases, including
FTD. Evidence suggests that neurodegenerative diseases cause circadian/sleep dysfunction, while
circadian/sleep disturbances can accelerate disease progression. However, the molecular and cellular
mechanisms linking neurodegenerative diseases to circadian and sleep disruptions are not well understood.
We propose to perform an unbiased genome-wide screen in Drosophila to identify candidate molecular
pathways underlying the association between FTD and circadian dysfunction. We will focus on the GGGGCC
(G4C2) nucleotide repeat expansion (NRE) in C9orf72 (C9), the most common genetic mutation causing FTD
and amyotrophic lateral sclerosis, two overlapping diseases on a neurodegenerative spectrum. The C9-NRE
mutation leads to the accumulation of highly toxic arginine-rich dipeptide repeats (DPRs). Preliminary data
show that expressing G4C2 repeats or DPRs in Drosophila leads to circadian period lengthening and reduced
rhythmicity. The circadian deficits occur before clock neuron degeneration, which provides exciting opportunity
to discover C9-interacting molecules acting in the early stages of FTD pathogenesis. In Aim 1, we will conduct
an unbiased genome-wide screen using a collection of deficiencies (deletions that remove multiple genes),
which provides 98.3% coverage of the entire Drosophila genome with only 474 deficiencies. In Aim 2, we will
determine the role of the Toll pathway in the C9 pathologies. We discovered the conserved Toll signaling
pathway as a modifier of C9-linked circadian phenotypes in our preliminary examination of candidate genes.
The Toll pathway has highly conserved roles in innate immunity and is also implicated in circadian regulation.
However, whether the Toll pathway plays a role in C9-linked diseases is unknown. Our study will identify novel
genetic modifiers of C9-related circadian dysfunction and provide new insights into the links between FTD,
circadian rhythms, and innate immunity.
Terms: <21+ years old><AD related dementia><ADRD><ALS patients><Acceleration><Adult><Adult Human><Alzheimer's and related dementias><Alzheimer's disease and related dementia><Alzheimer's disease and related disorders><Alzheimer's disease or a related dementia><Alzheimer's disease or a related disorder><Alzheimer's disease or related dementia><Alzheimer's disease related dementia><Amentia><Amyotrophic Lateral Sclerosis patients><Amyotrophic lateral sclerosis and frontotemporal degeneration><Amyotrophic lateral sclerosis and frontotemporal dementia><Appearance><Arginine><Basal Transcription Factor><Basal transcription factor genes><Biological Function><Biological Process><C9ORF72><Cactaceae><Cactus><Candidate Disease Gene><Candidate Gene><Cell Communication and Signaling><Cell Signaling><Circadian Dysregulation><Circadian Rhythms><Clock protein><Collection><Cyclicity><DNA Alteration><DNA Sequence Alteration><DNA mutation><Data><Defect><Degenerative Neurologic Disorders><Dementia><Dipeptides><Disease><Disease Progression><Disorder><Dose><Double-Stranded RNA><Down-Regulation><Drosophila><Drosophila genome><Drosophila genus><Eye><Eyeball><FTD/ALS><FTLD/ALS><Flies><Frontal Temporal Dementia><Frontotemporal Dementia><Frontotemporal Lobar Degeneration/Amyotrophic lateral sclerosis><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Screening><Genetic defect><Genetic mutation><Genome><Heterozygote><Human><Huntington Chorea><Huntington Disease><Huntington's><Huntington's Disease><Huntingtons Disease><Immunoglobulin Enhancer-Binding Protein><Individual><Innate Immunity><Intracellular Communication and Signaling><L-Arginine><L-Proline><Link><Mediating><Modeling><Modern Man><Modification><Molecular><Mutation><NF-kB><NF-kappa B><NF-kappaB><NFKB><Native Immunity><Natural Immunity><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neuron Degeneration><Neurons><Non-Polyadenylated RNA><Non-Specific Immunity><Nonspecific Immunity><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Nucleotides><Nyctohemeral Rhythm><Ortholog><Orthologous Gene><Pathogenesis><Pathology><Pathway interactions><Patients><Periodicity><Persons><Phenotype><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Proline><Proteins><RNA><RNA Gene Products><RNA Interference><RNA Silencing><RNAi><Receptor Protein><Receptor Signaling><Research><Rhythmicity><Ribonucleic Acid><Role><Sequence Alteration><Sequence-Specific Posttranscriptional Gene Silencing><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Sleep Disorders><Sleep Wake Cycle><Sleep disturbances><System><TLR protein><Testing><Toll-Like Receptor Family Gene><Toll-Like Receptor Pathway><Toll-like receptors><Toxic effect><Toxicities><Transcription Factor NF-kB><Transcription Factor Proto-Oncogene><Transcription factor genes><Twenty-Four Hour Rhythm><Work><aberrant sleep><adulthood><amyotrophic lateral sclerosis with frontotemporal dementia><amyotrophic lateral sclerosis/FTLD><amyotrophic lateral sclerosis/frontotemporal dementia><amyotrophic lateral sclerosis/ftd><anti-microbial><antimicrobial><behavior phenotype><behavioral phenotyping><biological signal transduction><candidate identification><cellular pathology><chromosome 9 open reading frame 72><circadian><circadian abnormality><circadian clock><circadian disruption><circadian disturbance><circadian dysfunction><circadian impairment><circadian pacemaker><circadian process><circadian regulation><daily biorhythm><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><disease model><disorder model><disrupted sleep><disturbed sleep><dsRNA><fly><front temporal dementia><frontal lobe dementia><frontotemporal dementia-amyotrophic lateral sclerosis><frontotemporal lobar dementia><frontotemporal lobar dementia amyotrophic lateral sclerosis><frontotemporal lobe degeneration associated with dementia><fruit fly><fruit fly genome><gain of function><gene null><genome mutation><genome wide screen><genomic alteration><heterozygosity><impaired sleep><insight><irregular sleep><kappa B Enhancer Binding Protein><knock-down><knockdown><neural degeneration><neurodegeneration><neurodegenerative><neurodegenerative illness><neurological degeneration><neuronal><neuronal degeneration><new marker><novel><novel biomarker><novel marker><nuclear factor kappa beta><null mutation><overexpress><overexpression><pathway><receptor><sleep diseases><sleep disruption><sleep dysfunction><sleep dysregulation><sleep illness><sleep problem><social role><transcription factor>