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Principal Investigator: Olena Korvatska
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2024
Award: $759,146
Funding agency: National Institute on Aging
Alzheimer's disease (AD), the most frequent cause of age-related dementia, constitutes a serious burden for
the US health system and economy. In the absence substantial preventative or disease-modifying treatments,
AD frequency is increasing as the lifespan increases. Age and genetic predisposition are the largest contributors
to AD risk. A substantial fraction of genetic variation in AD are noncoding variants that regulate gene expression,
but unlike changes in protein code, impact of regulatory variants is not easily predictable. Currently known genes
and risk alleles that change protein coding sequence explain at most 30% of AD susceptibility, emphasizing the
need to investigate variants that regulate gene expression and splicing. According to recent estimates, up to
50% of all variants associated with human diseases are variants that have some effect on gene splicing.
Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific immune molecule whose
dysfunction causes a continuum of neurodegenerative conditions. Some missense TREM2 variants, exemplified
by R47H, are transmitted as autosomal dominant traits, conferring a significant late onset AD risk. The R47H
allele is one of the strongest known contributors to the risk, with effect size similar to the APOE e4 allele. On the
other hand, biallelic loss-of-function variants that inactivate the receptor cause recessive early onset dementia,
such as Nasu-Hakola disorder (NHD). TREM2 is subject to alternative splicing, which is species-specific, but the
extent and effect of this process has yet to be comprehensively characterized. We recently identified a novel
splice isoform of TREM2 (delta e2) with altered activities due to lack of an important protein domain. In
preliminary study, we found that multiple variants that cause NHD or increase risk for AD affect TREM2 splicing
and reduce the dosage of functional transcript via competition with the abnormally spliced delta e2 isoform. We
hypothesize that a precise balance of isoforms is important for TREM2 function and that cis-regulatory variants,
in combination with protein factors variably expressed in AD microglia, reduce gene dosage and increase AD
risk. The goal of this proposal is to comprehensively characterize the TREM2 transcript repertoire in human brain
in health and disease (Aim 1), assess TREM2 variants that are present in patients with dementia for their effect
on RNA splicing and post-splicing processing (Aim 2) and analyze the interplay between AD-associated cis-
regulatory TREM2 variants and trans-acting splicing factors that are perturbed in AD brain (Aim 3). To achieve
these goals, we will use state-of-the-art long-read RNA sequencing, computational variant effect predictions,
high-throughput combinatorial library screening, and unbiased quantitative proteomics approaches. This will
generate a cis-regulatory TREM2 map at the nucleotide resolution level that will be used to annotate the
regulatory potential of hundreds of variants of unknown significance found in AD patients. Successful completion
of the proposal will spearhead application of similar strategies to characterize variants that affect post-
transcriptional regulation of other disease-related genes.
Terms: <3' Untranslated Regions><3'UTR><AD dementia><AD pathology><APOE e4><APOE-ε4><APOEε4><Address><Affect><African><African American group><African American individual><African American people><African American population><African Americans><Age><Alleles><Allelic Loss><Allelomorphs><Alternate Splicing><Alternative RNA Splicing><Alternative Splicing><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's brain><Alzheimer's disease brain><Alzheimer's disease pathology><Alzheimer's disease patient><Alzheimer's disease risk><Alzheimer's pathology><Alzheimer's patient><Alzheimers Dementia><Amentia><Assay><Binding><Bioassay><Biological Assay><Brain><Brain Nervous System><Brain region><Code><Coding System><Codon><Codon Nucleotides><Complex><Consensus><Defect><Degenerative Neurologic Disorders><Dementia><Diathesis><Differences between sexes><Differs between sexes><Disease><Disease susceptibility><Disorder><Dysfunction><Elderly><Encephalon><Equilibrium><European><Event><Frequencies><Frontal Temporal Dementia><Frontotemporal Dementia><Functional RNA><Functional disorder><Gene Action Regulation><Gene Copy Number><Gene Dosage><Gene Expression><Gene Expression Regulation><Gene Proteins><Gene Regulation><Gene Regulation Process><Gene Splicing><Gene variant><Genes><Genetic Diseases><Genetic Diversity><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Susceptibility><Genetic Variation><Genetic propensity><Goals><Health><Health system><Heterozygote><Hortega cell><Human><Immune><Immune signaling><Immunes><Immunologic Receptors><Immunological Receptors><Increase lifespan><Inherited Predisposition><Inherited Susceptibility><Intervening Sequences><Introns><Isoforms><Knowledge><Late Onset Alzheimer Disease><Libraries><Link><Loss of Heterozygosity><Macrophage><Maps><Messenger RNA><Microglia><Modern Man><Molecular Interaction><Mφ><Nerve Degeneration><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neuron Degeneration><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Nucleotides><Pathogenicity><Pathology><Patients><Peptide Domain><Persons><Phenotype><Physiopathology><Post-Transcriptional Control><Post-Transcriptional Regulation><Pre-mRNA><Predisposition><Preventative therapy><Preventive therapy><Primary Senile Degenerative Dementia><Process><Protein Domains><Protein Gene Products><Protein Isoforms><Proteins><Proteomics><RNA Seq><RNA Splicing><RNA sequencing><RNA, Messenger, Precursors><RNA-Binding Proteins><RNAseq><Receptor Protein><Receptor Signaling><Reporter><Research Design><Research Resources><Resolution><Resources><Risk><Risk Factors><Risk-associated variant><Role><Sex Differences><Sexual differences><Spliced Genes><Spliceosomes><Splicing><Stop Codon><Study Type><Surface><Susceptibility><TREM2><TREM2 gene><Termination Codon><Terminator Codon><Tertiary Protein Structure><Testing><Trans-Acting Factors><Trans-Activators><Transactivators><Transcript><Translation Stop Signal><Translations><Transmission><Triggering Receptor Expressed in Myeloid Cells 2><Triggering Receptor Expressed on Myeloid Cells 2><Untranslated RNA><Variant><Variation><Work><advanced age><age associated><age correlated><age dependent><age linked><age related><age specific><ages><allele variant><allelic variant><alzheimer risk><apo E-4><apo E4><apo epsilon4><apoE epsilon 4><apoE-4><apoE4><apolipoprotein E epsilon 4><apolipoprotein E-4><apolipoprotein E4><autosomal dominant trait><balance><balance function><combinatorial><curative intervention><curative therapeutic><curative therapy><curative treatments><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><dementia risk><dosage><early onset><elongating the lifespan><exon skipping><experimental analysis><extend life span><extend lifespan><front temporal dementia><frontal lobe dementia><frontotemporal lobar dementia><frontotemporal lobe degeneration associated with dementia><genetic condition><genetic disorder><genetic etiology><genetic mechanism of disease><genetic variant><genetic vulnerability><genetically predisposed><genomic variant><geriatric><gitter cell><health economics><heterozygosity><human disease><immune receptor><in silico><late onset alzheimer><liability to disease><lifespan extension><loss of function><mRNA><mRNA Precursor><mesoglia><microglial cell><microgliocyte><neural degeneration><neurodegeneration><neurodegenerative><neurodegenerative illness><neurological degeneration><neuronal degeneration><non-demented><noncoding><nondemented><novel><pathophysiology><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><perivascular glial cell><post-transcriptional gene regulation><posttranscriptional><posttranscriptional control><posttranscriptional regulation><predictive tools><premature><prematurity><primary degenerative dementia><protein function><receptor><resolutions><risk allele><risk factor for dementia><risk for dementia><risk gene><risk genotype><risk loci><risk locus><risk variant><screening><screenings><senile dementia of the Alzheimer type><senior citizen><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><social role><study design><synthetic biology><transcriptome sequencing><transcriptomic sequencing><translation><transmission process><unclassified variant><variant of uncertain clinical significance><variant of uncertain significance><variant of undetermined significance><variant of unknown significance>