A5046014282- Alzheimer's disease research and treatments
- Cellular transport and secretion
- Neuroinflammation and Neurodegeneration Mechanisms
- Pluripotent Stem Cells Research
- Cholinesterase and Neurodegenerative Diseases
- Bioinformatics and Genomic Networks
- Nuclear Receptors and Signaling
- Retinal Development and Disorders
- CRISPR and Genetic Engineering
- Genetic Neurodegenerative Diseases
- Computational Drug Discovery Methods
- Neuroscience and Neural Engineering
- 3D Printing in Biomedical Research
- Neurogenesis and neuroplasticity mechanisms
- RNA Research and Splicing
- Dementia and Cognitive Impairment Research
- Single-cell and spatial transcriptomics
- Histone Deacetylase Inhibitors Research
- Parkinson's Disease Mechanisms and Treatments
- Mitochondrial Function and Pathology
- Neurogenetic and Muscular Disorders Research
- Machine Learning in Bioinformatics
- Genetics, Aging, and Longevity in Model Organisms
- Immune cells in cancer
- Neurological Disease Mechanisms and Treatments
University of Washington
2007-2025
California Institute for Regenerative Medicine
2021-2024
Seattle University
2022
Institute for Stem Cell Biology and Regenerative Medicine
2022
University of California, San Diego
2013-2018
Sanford Consortium for Regenerative Medicine
2012
Howard Hughes Medical Institute
2011
Mayo Clinic in Florida
2008-2009
Royal University Hospital
2009
University of Saskatchewan
2009
Loss of the Sortilin-related receptor 1 (SORL1) gene seems to act as a causal event for Alzheimer's disease (AD). Recent studies have established that loss SORL1, well mutations in autosomal dominant AD genes APP and PSEN1/2, pathogenically converge by swelling early endosomes, AD's cytopathological hallmark. Acting together with retromer trafficking complex, SORL1 has been shown regulate recycling amyloid precursor protein (APP) out endosome, contributing endosomal misprocessing. We...
Abstract Microglia, the innate immune cells of brain, influence Alzheimer’s disease (AD) progression and are potential therapeutic targets. However, microglia exhibit diverse functions, regulation which is not fully understood, complicating therapeutics development. To better define transcriptomic phenotypes gene regulatory networks associated with AD, we enriched for nuclei from 12 AD 10 control human dorsolateral prefrontal cortices (7 males 15 females, all aged >60 years) before...
Huntington's disease (HD) is a neurodegenerative disorder caused by polyglutamine (polyQ) tract expansion near the N terminus of huntingtin (Htt). Proteolytic processing mutant Htt and abnormal calcium signaling may play critical role in progression pathogenesis. Recent work indicates that calpains participate increased and/or altered patterns proteolysis leading to selective toxicity observed HD striatum. Here, we identify two calpain cleavage sites show mutation these renders polyQ...
Presenilin 1 (PS1) is the catalytic core of γ-secretase, which cleaves type transmembrane proteins, including amyloid precursor protein (APP). PS1 also has γ-secretase-independent functions, and dominant missense mutations are most common cause familial Alzheimer's disease (FAD). Whether FAD gain- or loss-of-function remains controversial, primarily because studies have relied on overexpression in mouse and/or nonneuronal systems. We used isogenic euploid human induced pluripotent stem cell...
Spinal and bulbar muscular atrophy (SBMA) is a progressive neurodegenerative disease caused by an expansion of the polyglutamine tract in androgen receptor (AR). Here, we investigated regulation AR phosphorylation order to understand factors that may modify SBMA progression. We show expanded phosphorylated Akt. Substitution at two Akt consensus sites, S215 S792, with aspartate, which mimics phosphorylation, reduces ligand binding, ligand-dependent nuclear translocation, transcriptional...
SORL1/SORLA is a sorting receptor involved in retromer-related endosomal traffic and an Alzheimer's disease (AD) risk gene. Using CRISPR-Cas9, we deplete SORL1 hiPSCs to ask if loss of contributes AD pathogenesis by endosome dysfunction. SORL1-deficient hiPSC neurons show early enlargement, hallmark cytopathology AD. There no effect depletion on size microglia, suggesting selective neuronal trafficking. We validate defects showing altered localization amyloid precursor protein (APP)...
Highlights•FAD mutations impair endocytosis and transcytosis of APP lipoproteins•Reduced lipoprotein are rescued by β-secretase inhibitionSummaryWe investigated early phenotypes caused familial Alzheimer's disease (fAD) in isogenic human iPSC-derived neurons. Analysis neurons carrying fAD PS1 or introduced using genome editing technology at the endogenous loci revealed that mutant had previously unreported defects recycling state soma-to-axon lipoproteins. The reduction could be through...
Developing effective therapeutics for complex diseases such as late-onset, sporadic Alzheimer's disease (SAD) is difficult due to genetic and environmental heterogeneity in the human population limitations of existing animal models. Here, we used hiPSC-derived neurons test a compound that stabilizes retromer, highly conserved multiprotein assembly plays pivotal role trafficking molecules through endosomal network. Using this human-specific system, have confirmed previous data generated...
SORL1 is implicated in the pathogenesis of Alzheimer's disease (AD) through genetic studies. To interrogate roles human brain cells, SORL1-null induced pluripotent stem cells (iPSCs) were differentiated to neuron, astrocyte, microglial, and endothelial cell fates. Loss leads alterations both overlapping distinct pathways across types, with greatest effects neurons astrocytes. loss induces a neuron-specific reduction apolipoprotein E (APOE) clusterin (CLU) altered lipid profiles. Analyses...
Abstract Background X chromosome inactivation (XCI) is a female-specific process in which one silenced to balance X-linked gene expression between the sexes. XCI initiated early development by upregulation of lncRNA Xist on future inactive (Xi). A subset genes escape silencing and thus have higher females, suggesting functions. One these highly conserved Kdm6 a, encodes histone demethylase that removes methyl groups at H3K27 facilitate expression. KDM6A mutations been implicated congenital...
Although autophagy maintains normal neural function by degrading misfolded proteins, little is known about how neurons activate this integral response. Furthermore, classical methods of induction used with nonneural cells, such as starvation, simply result in neuron death. To study neuronal autophagy, we cultured primary cortical from transgenic mice that ubiquitously express green fluorescent protein-tagged LC3 and monitored LC3-I to LC3-II conversion immunohistochemistry immunoblotting....
Spinocerebellar ataxia type 7 (SCA7) is a polyglutamine (polyQ) disorder characterized by specific degeneration of cerebellar, brainstem, and retinal neurons. Although they share little sequence homology, proteins implicated in polyQ disorders have common properties beyond their characteristic tract. These include the production proteolytic fragments, nuclear accumulation, processing caspases. Here we report that ataxin-7 cleaved caspase-7, map two putative caspase-7 cleavage sites to Asp...
Hydrogen Peroxide (H2O2) is a central oxidant in redox biology due to its pleiotropic role physiology and pathology. However, real-time monitoring of H2O2 living cells tissues remains challenge. We address this gap with the development an optogenetic hydRogen perOxide Sensor (oROS), leveraging bacterial peroxide binding domain OxyR. Previously engineered OxyR-based fluorescent sensors lack necessary sensitivity or response speed for effective monitoring. By structurally redesigning fusion...
The endosomal gene
Spinal and bulbar muscular atrophy (SBMA) is an inherited neuromuscular disorder caused by a polyglutamine (polyQ) repeat expansion in the androgen receptor (AR). PolyQ-AR neurotoxicity may involve generation of N-terminal truncation fragment, as such peptides occur SBMA patients mouse models. To elucidate basis SBMA, we expressed truncated AR motor neuron-derived cells primary cortical neurons. Accumulation polyQ-AR fragments cytosol resulted neurodegeneration apoptotic, caspase-dependent...