A5009471491- Alzheimer's disease research and treatments
- RNA Research and Splicing
- Amyotrophic Lateral Sclerosis Research
- Genetics, Aging, and Longevity in Model Organisms
- RNA regulation and disease
- Cholinesterase and Neurodegenerative Diseases
- Parkinson's Disease Mechanisms and Treatments
- Mitochondrial Function and Pathology
- Prion Diseases and Protein Misfolding
- Gene Regulatory Network Analysis
- Genetic Neurodegenerative Diseases
- Nanoparticles: synthesis and applications
- Nuclear Structure and Function
- Mass Spectrometry Techniques and Applications
- CRISPR and Genetic Engineering
- MicroRNA in disease regulation
- Viral Infectious Diseases and Gene Expression in Insects
- Endoplasmic Reticulum Stress and Disease
- Microtubule and mitosis dynamics
- Nuclear Receptors and Signaling
- Biochemical and Molecular Research
- Histone Deacetylase Inhibitors Research
- Analytical Chemistry and Sensors
- Blood disorders and treatments
- Signaling Pathways in Disease
University of Puget Sound
2014-2023
VA Puget Sound Health Care System
2016-2022
Geriatric Research Education and Clinical Center
2014-2022
University of Washington
2010-2014
Seattle University
2010
Pathological aggregates of phosphorylated TDP-43 characterize amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), two devastating groups neurodegenerative disease. Kinase hyperactivity may be a consistent feature ALS FTLD-TDP, as is not observed in the absence neurodegeneration. By examining changes phosphorylation state, we have identified kinases controlling C. elegans model ALS. In this kinome-wide survey, homologs tau tubulin 1 2 (TTBK1 TTBK2), which...
Progressive neuron loss in the frontal and temporal lobes of cerebral cortex typifies frontotemporal lobar degeneration (FTLD). FTLD sub types are classified on basis neuronal aggregated protein deposits, typically containing either aberrantly phosphorylated TDP-43 or tau. Our recent work demonstrated that tau tubulin kinases 1 2 (TTBK1/2) robustly phosphorylate co-localize with human postmortem neurons from patients. Both TTBK1 TTBK2 were initially identified as has been shown to epitopes...
Aggregates of Aβ peptide and the microtubule-associated protein tau are key molecular hallmarks Alzheimer's disease (AD). However, interaction between these two pathologies mechanisms underlying progression have remained unclear. Numerous failed clinical trials suggest necessity for greater mechanistic understanding in order to refine strategies therapeutic discovery development. To this end, we generated a transgenic Caenorhabditis elegans model expressing both human Aβ1-42 pan-neuronally....
Abstract To endure over the organismal lifespan, neurons utilize multiple strategies to achieve protein homeostasis (proteostasis). Some homeostatic mechanisms act in a subcellular compartment-specific manner, but others exhibit trans-compartmental of proteostasis. identify pathways protecting from pathological tau protein, we employed transgenic Caenorhabditis elegans model human tauopathy exhibiting proteostatic disruption. We show normal functioning endoplasmic reticulum unfolded response...
Abstract Several conserved nuclear RNA binding proteins ( sut-1, sut-2, and parn-2 ) control tau aggregation toxicity in C. elegans , mice, human cells. MSUT2 protein normally resides speckles, membraneless organelles composed of phase-separated RNAs RNA-binding that mediate critical steps mRNA processing including splicing. We used pathological tissue transgenic mice to identify Alzheimer’s disease-specific cellular changes related speckles. observed speckle constituent scaffold SRRM2 is...
Abstract Alzheimer’s disease and related disorders feature neurofibrillary tangles other neuropathological lesions composed of detergent-insoluble tau protein. In recent structural biology studies proteinopathy, aggregated forms a distinct set conformational variants specific to the different types tauopathy disorders. However, constituents driving formation pathological conformations on pathway tau-mediated neurodegeneration remain unknown. Previous work demonstrated RNA can serve as driver...
Achieving precise control of mammalian transgene expression has remained a long-standing, and increasingly urgent, challenge in biomedical science. Despite much work, single-cell methods have consistently revealed that gene levels remain susceptible to fluctuations (noise) external perturbations. Here, we show protein synthesis can be realized using single-gene microRNA (miRNA)-based feed-forward loop (sgFFL). This minimal autoregulatory circuit consists an intronic miRNA targets its own...
The poly(A) RNA binding proteins MSUT2 and PABPN1 regulate the accumulation of pathological tau in two mouse models tauopathy.
Neurofibrillary tangles composed of aberrantly aggregating tau protein are a hallmark Alzheimer's disease and related dementia disorders. Recent work has shown that mammalian suppressor tauopathy 2 (MSUT2), also named ZC3H14 (Zinc Finger CCCH-Type Containing 14), controls accumulation pathological in cultured human cells mice. Knocking out
Oxygen consumption is a fundamental component of metabolic networks, mitochondrial function, and global carbon cycling. To date there no method available that allows for replicate measurements on attached unattached biological samples without compensation extraneous oxygen leaking into the system. Here we present Respiratory Detection System, which compatible with virtually any sample. The RDS can be used to measure uptake in microliter-scale volumes reversibly sealed sample chamber,...
Pathological phosphorylated TDP-43 protein (pTDP) deposition drives neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). However, the cellular genetic mechanisms at work pathological toxicity are not fully elucidated. To identify modifiers of neurotoxicity, we utilized a Caenorhabditis elegans model proteinopathy expressing human mutant pan-neuronally (TDP-43 tg). In tg C. elegans, conducted genome-wide RNAi screen covering 16,767 genes...
Aging drives pathological accumulation of proteins such as tau, causing neurodegenerative dementia disorders like Alzheimer's disease. Previously we showed loss function mutations in the gene encoding poly(A) RNA binding protein SUT-2/MSUT2 suppress tau-mediated neurotoxicity C. elegans neurons, cultured human cells, and mouse brain, while PABPN1 had opposite effect (Wheeler et al., 2019). Here found that blocking tail extension with cordycepin exacerbates tauopathy which is rescued by MSUT2...
Tauopathies are neurological disorders characterized by intracellular tau deposits forming neurofibrillary tangles, neuropil threads, or other disease-specific aggregates composed of the protein tau. Tauopathy include frontotemporal lobar degeneration, corticobasal Pick's disease, and largest cause dementia, Alzheimer's disease. The lack disease-modifying therapeutic strategies to address tauopathies remains a critical unmet need in dementia care. Thus, novel broad-spectrum tau-targeted...
Abstract Background Aggregates of Aβ peptide and the microtubule‐associated protein tau are key molecular hallmarks Alzheimer's disease (AD). However, interaction between these two pathologies mechanisms underlying progression have remained unclear. Numerous failed clinical trials suggest necessity for greater mechanistic understanding in order to refine strategies therapeutic discovery development. Method To this end, we generated a transgenic Caenorhabditis elegans model expressing both...
Abstract Background Pathological tau characterizes Alzheimer’s disease, FTLD‐tau, and other tauopathy disorders. Canonically, functions as a microtubule binding stabilizing protein. The molecular mechanisms of mediated neurodegeneration remain incompletely understood. Recent studies from our group others have shown that RNA proteins modulate the severity pathology. Further, has previously been demonstrated to drive aggregation in vitro. We hypothesize itself may interact physically with...