A5011617410- Ubiquitin and proteasome pathways
- Autophagy in Disease and Therapy
- Cellular transport and secretion
- Genetics and Neurodevelopmental Disorders
- Lysosomal Storage Disorders Research
- Alzheimer's disease research and treatments
- Hair Growth and Disorders
- melanin and skin pigmentation
- Calcium signaling and nucleotide metabolism
- Parkinson's Disease Mechanisms and Treatments
- Epigenetics and DNA Methylation
- RNA Research and Splicing
- interferon and immune responses
- Genomics and Chromatin Dynamics
- Endoplasmic Reticulum Stress and Disease
- Signaling Pathways in Disease
- Histone Deacetylase Inhibitors Research
- ATP Synthase and ATPases Research
- Biocrusts and Microbial Ecology
- Hormonal and reproductive studies
- RNA Interference and Gene Delivery
- Redox biology and oxidative stress
- Urticaria and Related Conditions
- NF-κB Signaling Pathways
- Mass Spectrometry Techniques and Applications
Nathan Kline Institute for Psychiatric Research
2016-2024
NYU Langone Health
2021-2024
Solid (South Korea)
2024
New York University
2016-2023
Yonsei University
2010-2020
Korea Institute of Science and Technology
2019
Google (United States)
2016
Autophagy is markedly impaired in Alzheimer's disease (AD). Here we reveal unique autophagy dysregulation within neurons five AD mouse models vivo and identify its basis using a neuron-specific transgenic mRFP-eGFP-LC3 probe of pH, multiplex confocal imaging correlative light electron microscopy. Autolysosome acidification declines well before extracellular amyloid deposition, associated with lowered vATPase activity build-up Aβ/APP-βCTF selectively enlarged de-acidified autolysosomes. In...
Lysosomal failure underlies pathogenesis of numerous congenital neurodegenerative disorders and is an early progressive feature Alzheimer9s disease (AD) pathogenesis. Here, we report that lysosomal dysfunction in Down ayndrome (trisomy 21), a neurodevelopmental disorder form onset AD, requires the extra gene copy amyloid precursor protein (APP) specifically mediated by β cleaved carboxy terminal fragment APP (APP-βCTF, C99). In primary fibroblasts from individuals with DS, degradation...
Lysosome dysfunction arises early and propels Alzheimer's disease (AD). Herein, we show that amyloid precursor protein (APP), linked to early-onset AD in Down syndrome (DS), acts directly via its β-C-terminal fragment (βCTF) disrupt lysosomal vacuolar (H+)-adenosine triphosphatase (v-ATPase) acidification. In human DS fibroblasts, the phosphorylated 682YENPTY internalization motif of APP-βCTF binds selectively within a pocket v-ATPase V0a1 subunit cytoplasmic domain competitively inhibits...
Autophagy-lysosome pathway (ALP) disruption is considered pathogenic in multiple neurodegenerative diseases; however, current methods are inadequate to investigate macroautophagy/autophagy flux brain vivo and its therapeutic modulation. Here, we describe a novel autophagy reporter mouse (TRGL6) stably expressing dual-fluorescence-tagged LC3 (tfLC3, mRFP-eGFP-LC3) by transgenesis selectively neurons. The tfLC3 probe distributes widely the central nervous system, including spinal cord....
Parkinson's disease (PD) is a common neurodegenerative that involves the deterioration of dopaminergic neurons in substantia nigra pars compacta. Although etiology PD remains poorly understood, recent genetic, postmortem, and experimental evidence shows abnormal protein accumulation subsequent aggregate formation are prominent features both sporadic familial PD. While proteasome dysfunction observed PD, diverse mutations parkin gene linked to early-onset autosomal-recessive forms We...
Parkinson's disease (PD) is characterized by selective loss of dopaminergic neurons in the pars compacta substantia nigra and accumulation ubiquitinated proteins aggregates called Lewy bodies. Several mutated genes have been found familial PD patients, including SNCA (α-synuclein), PARK2 (parkin), PINK1, PARK7 (DJ-1), LRRK2 ATP13A2 Many pathogenic mutations PARK2, which encodes ubiquitin E3 ligase parkin, result function, leading to parkin substrates consequently contributing cell death....
Abstract Mutations in the parkin gene underlie a familial form of Parkinson's disease known as autosomal recessive juvenile Parkinsonism (AR‐JP). Dysfunction parkin, ubiquitin E3 ligase, has been implicated accumulation proteasome system‐destined substrates and eventually leads to cell death. However, regulation enzymatic activity is incompletely understood. Here we investigated whether ligase could be regulated by neddylation. We found that target covalent modification with NEDD8,...
The 26 S proteasome, composed of the 20 core and 19 regulatory particle, plays a central role in ubiquitin-dependent proteolysis. Disruption this process contributes to pathogenesis various diseases; however, mechanisms underlying regulation proteasome activity remain elusive. Here, cell culture experiments <i>in vitro</i> assays demonstrated that apoptosis signal-regulating kinase 1 (ASK1), member MAPK family, negatively regulated activity. Immunoprecipitation/Western blot analyses revealed...
Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase, an RNA‐dependent DNA polymerase that elongates telomeric DNA. hTERT displays several extra‐telomeric functions are independent its telomere‐regulatory function, including tumor progression, and neuronal cell death regulation. In this study, we evaluated these additional non‐telomeric functions. We determined interacts with 19S 20S proteasome subunits. The regulatory particle core part 26S complex, which...
Mutations of parkin are associated with the occurrence autosomal recessive familial Parkinson's disease (PD). Parkin acts an E3 ubiquitin ligase, which ubiquitinates target proteins and subsequently regulates either their steady-state levels through ubiquitin-proteasome system or biochemical properties. In this study, we identify a novel regulatory mechanism by searching for new factors. After screening human fetal brain using yeast two hybrid assay, found dual-specificity...
Similar to ubiquitin, regulatory roles for NEDD8 (neural precursor cell-expressed developmentally down-regulated 8) are being clarified during cell growth, signal transduction, immune response, and development. However, targets their functional alterations not well known. Regulator of calcineurin 1 (RCAN1/DSCR1P1) is located near the Down syndrome critical region on distal part chromosome 21, its gene product an endogenous inhibitor signaling. RCAN1 modified by ubiquitin consequently...
Down syndrome (DS) is mainly caused by an extra copy of chromosome 21 (trisomy 21), and patients display a variety developmental symptoms, including characteristic facial features, physical growth delay, intellectual disability, neurodegeneration (i.e., Alzheimer's disease; AD). One the pathological hallmarks AD insoluble deposits neurofibrillary tangles (NFTs) that consist hyperphosphorylated tau. The human DYRK1A gene mapped to 21, protein associated with formation inclusion bodies in AD....
Abstract Much is still unknown about the neurobiology of Alzheimer’s disease (AD). To better understand AD, we generated 636 ATAC-seq libraries from cases and controls to construct detailed genomewide chromatin accessibility maps neurons non-neurons two AD-affected brain regions, entorhinal cortex superior temporal gyrus. By analyzing a total 19.6 billion read pairs, expanded known repertoire regulatory sequences in human brain. Multi-omic data integration associated global patterns with...
Regulator of calcineurin 1 (RCAN1; also referred as DSCR1 or MCIP1) is located in close proximity to a Down syndrome critical region human chromosome 21. Although RCAN1 an endogenous inhibitor signaling that controls lymphocyte activation, apoptosis, heart development, skeletal muscle differentiation, and cardiac function, it not yet clear whether might be involved other cellular activities. In this study, we explored the extra-functional roles by searching for novel RCAN1-binding partners....
Male pattern baldness (MPB) has been associated with dihydrotestosterone (DHT) expression. Finasteride treats MPB by inhibiting 5-alpha reductase and blocking DHT production. In this study, we aimed to identify metabolic differences in urinary metabolomics profiles between patients after a one-year treatment finasteride healthy controls. Untargeted targeted profiling was performed using liquid chromatography-mass spectrometry (LC-MS). We hypothesized that there would be changes overall...
Abstract Lysosome dysfunction arises early and propels Alzheimer’s Disease (AD). Herein, we show that amyloid precursor protein (APP), linked to early-onset AD in Down Syndrome (DS), acts directly via its β-C-terminal fragment (βCTF) disrupt lysosomal v-ATPase acidification. In human DS fibroblasts, the phosphorylated 682 YENPTY internalization motif of APP-βCTF binds selectively within a pocket V0a1 subunit cytoplasmic domain competitively inhibits association V1 subcomplex v-ATPase,...
Abstract Background Autophagy‐lysosomal pathway (ALP) dysfunction emerges early in Alzheimer’s disease(AD). In mouse AD models, lysosomal acidification deficits impair ALP neurons, some inducing massive autolysosome accumulations, intraneuronal amyloid plaque, and neuronal death yielding an extracellular plaque. This distinctive neurodegenerative pattern (PANTHOS) early‐stage is recapitulated human late‐onset (accompanying poster). Restoring acidity via β2‐adrenergic receptor (β2‐AR)...
Lysosome dysfunction arises early and propels Alzheimer’s Disease (AD). Herein, we show that amyloid precursor protein (APP), linked to early-onset AD in Down Syndrome (DS), acts directly via its β-C-terminal fragment (βCTF) disrupt lysosomal v-ATPase acidification. In human DS fibroblasts or brains of model mice, the phosphorylated682 YENPTY internalization motif APP-βCTF binds selectively within a pocket V0a1 subunit cytoplasmic domain competitively inhibits association with V1 subcomplex...