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김윤환,심현수,김경헌,이정희,정봉철,Neil W Kowall,류훈,이정애 한국뇌신경과학회 2019 Experimental Neurobiology Vol.28 No.3
Despite significant advances in neuroscience research over the past several decades, the exact cause of AD has not yet fully understood. The metabolic hypothesis as well as the amyloid and tau hypotheses have been proposed to be associated with AD pathogenesis. In order to identify metabolome signatures from the postmortem brains of sporadic AD patients and control subjects, we performed ultra performance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometer (UPLC-LTQ–OrbitrapMS). Not only our study identified new metabolome signatures but also verified previously known metabolome profiles in the brain. Statistical modeling of the analytical data and validation of the structural assignments discovered metabolic biomarkers associated with the AD pathogenesis. Interestingly, hypotaurin, myo-inositol and oxo-proline levels were markedly elevated in AD while glutamate and N-acetyl-aspartate were decreased in the postmortem brain tissue of AD patients. In addition, neurosteroid level such as cortisol was significantly increased in AD. Together, our data indicate that impaired amino acid metabolism is associated with AD pathogenesis and the altered amino acid signatures can be useful diagnostic biomarkers of AD. Thus, modulation of amino acid metabolism may be a possible therapeutic approach to treat AD.
Lee, Junghee,Kannagi, Mari,Ferrante, Robert J.,Kowall, Neil W.,Ryu, Hoon Federation of American Society for Experimental Bi 2009 The FASEB Journal Vol.23 No.6
<P>Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by selective degeneration of motor neurons and glial activation. Cell-specific transcriptional regulation induced by oxidative stress may contribute to the survival and activation of astrocytes in the face of motor neuron death. In the present study, we demonstrate an age-dependent increase in Bcl-xL and Ets-2 immunoreactivity that correlates with an increase of glial fibrillary acidic protein (GFAP)-positive cells in the ventral horn of the spinal cord in both ALS transgenic mice [mutant SOD1 (G93A)] and affected humans. Chromatin immunoprecipitation (ChIP) analysis verified that Ets-2 preferentially occupies the Ets-2 binding element in the promoter of Bcl-xL in primary astrocytes under oxidative stress conditions as well as in G93A spinal cords. Ets-2 small-interfering RNA down-regulated the transcriptional activity of Bcl-xL. In primary glial cultures, Bcl-xL overexpression and mutant SOD1 (G93A) both conferred resistance to oxidative stress-induced cell death. Our findings suggest that Ets-2 transcription factor activation of Bcl-xL gene may protect glia from constitutive oxidative stress that is thought to be a key mechanism contributing to the pathogenesis of ALS. This survival pathway may contribute to the glial survival and activation seen in the spinal cord of ALS patients.</P>
Lee, Jong Seok,Krause, Roland,Schreiber, Jö,rg,Mollenkopf, Hans-Joachim,Kowall, Jane,Stein, Robert,Jeon, Bo-Young,Kwak, Jeong-Yeon,Song, Min-Kyong,Patron, Juan Pablo,Jorg, Sabine,Roh, Kyoungmin,Ch Elsevier 2008 Cell host & microbe Vol.3 No.2
<P><B>Summary</B></P><P>Attenuated strains of mycobacteria can be exploited to determine genes essential for their pathogenesis and persistence. To this goal, we sequenced the genome of H37Ra, an attenuated variant of <I>Mycobacterium tuberculosis</I> H37Rv strain. Comparison with H37Rv revealed three unique coding region polymorphisms. One polymorphism was located in the DNA-binding domain of the transcriptional regulator PhoP, causing the protein's diminished DNA-binding capacity. Temporal gene expression profiles showed that several genes with reduced expression in H37Ra were also repressed in an H37Rv phoP knockout strain. At later time points, genes of the dormancy regulon, typically expressed in a state of nonreplicating persistence, were upregulated in H37Ra. Complementation of H37Ra with H37Rv <I>phoP</I> partially restored its persistence in a murine macrophage infection model. Our approach demonstrates the feasibility of identifying minute but distinct differences between isogenic strains and illustrates the consequences of single point mutations on the survival stratagem of <I>M. tuberculosis.</I></P>
Hwang, Yu Jin,Han, Dohyun,Kim, Ki Yoon,Min, Sun-Joon,Kowall, Neil W.,Yang, Liu,Lee, Junghee,Kim, Youngsoo,Ryu, Hoon Oxford University Press 2014 Nucleic acids research Vol.42 No.3
<P>The remodeling of chromatin in the nucleolus is important for the control of ribosomal DNA (rDNA) transcription and ribosome biogenesis. Herein, we found that upstream binding factor (UBF) interacts with ESET, a histone H3K9 methyltransferase and is trimethylated at Lys (K) 232/254 by ESET. UBF trimethylation leads to nucleolar chromatin condensation and decreased rDNA transcriptional activity. UBF mutations at K232/254A and K232/254R restored rDNA transcriptional activity in response to ESET. Both ESET-ΔSET mutant and knockdown of ESET by short hairpin RNA reduced trimethylation of UBF and resulted in the restoration of rDNA transcription. Atomic force microscopy confirmed that UBF trimethylated by ESET modulates the plasticity of nucleolar chromatin. We further demonstrated that UBF trimethylation at K232/254 by ESET deregulates rDNA transcription in a cell model of Huntington’s disease. Together, our findings show that a novel epigenetic modification of UBF is linked to impaired rDNA transcription and nucleolar chromatin remodeling, which may play key roles in the pathogenesis of neurodegeneration.</P>
Lee, Junghee,Nguyen, Phuong T.,Shim, Hyun Soo,Hyeon, Seung Jae,Im, Hyeonjoo,Choi, Mi-Hyun,Chung, Sooyoung,Kowall, Neil W.,Lee, Sean Bong,Ryu, Hoon Elsevier 2019 Biochimica et biophysica acta. Molecular basis of Vol.1865 No.7
<P><B>Abstract</B></P> <P>Ewing's sarcoma (EWS) is a bone cancer arising predominantly in young children. <I>EWSR1</I> (<I>Ewing Sarcoma breakpoint region 1</I>/<I>EWS RNA binding protein 1</I>) gene is ubiquitously expressed in most cell types, indicating it has diverse roles in various cellular processes and organ development. Recently, several studies have shown that missense mutations of <I>EWSR1</I> genes are known to be associated with central nervous system disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Otherwise, EWSR1 plays epigenetic roles in gene expression, RNA processing, and cellular signal transduction. Interestingly, EWSR1 controls micro RNA (miRNA) levels via Drosha, leading to autophagy dysfunction and impaired dermal development. <I>Ewsr1</I> deficiency also leads to premature senescence of blood cells and gamete cells with a high rate of apoptosis due to the abnormal meiosis. Despite these roles of EWSR1 in various cellular functions, the exact mechanisms are not yet understood. In this context, the current review overviews a large body of evidence and discusses on what <I>EWSR1</I> genetic mutations are associated with brain diseases and on how EWSR1 modulates cellular function via the epigenetic pathway. This will provide a better understanding of bona fide roles of EWSR1 in aging and its association with brain disorders.</P> <P><B>Highlights</B></P> <P> <UL> <LI> EWSR1 (Ewing Sarcoma breakpoint region 1/EWS RNA binding protein 1) has diverse roles in various cellular processes. </LI> <LI> Missense mutations of <I>EWSR1</I> are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). </LI> <LI> EWSR1 deficiency also contributes to hematopoietic stem cell senescence. </LI> <LI> EWSR1 participates in mitochondria function and cellular energy homeostasis by modulating the stability of PGC-1α. </LI> <LI> EWSR1 deficiency deregulates dopaminergic signaling pathways by reducing TH activity and leads to motor dysfunction. </LI> </UL> </P>
Baibin Bi,최한필,현승재,Shengnan Sun,Ning Su,Yuguang Liu,이정희,Neil W Kowall,Ann C McKee,Jing-Hua Yang,류훈 한국뇌신경과학회 2019 Experimental Neurobiology Vol.28 No.3
Chronic traumatic encephalopathy (CTE) is a distinct neurodegenerative disease that associated with repetitive head trauma. CTE is neuropathologically defined by the perivascular accumulation of abnormally phosphorylated tau protein in the depths of the sulci in the cerebral cortices. In advanced CTE, hyperphosphorylated tau protein deposits are found in widespread regions of brain, however the mechanisms of the progressive neurodegeneration in CTE are not fully understood. In order to identify which proteomic signatures are associated with CTE, we prepared RIPA-soluble fractions and performed quantitative proteomic analysis of postmortem brain tissue from individuals neuropathologically diagnosed with CTE. We found that axonal guidance signaling pathwayrelated proteins were most significantly decreased in CTE. Immunohistochemistry and Western blot analysis showed that axonal signaling pathway-related proteins were down regulated in neurons and oligodendrocytes and neuron-specific cytoskeletal proteins such as TUBB3 and CFL1 were reduced in the neuropils and cell body in CTE. Moreover, oligodendrocyte-specific proteins such as MAG and TUBB4 were decreased in the neuropils in both gray matter and white matter in CTE, which correlated with the degree of axonal injury and degeneration. Our findings indicate that deregulation of axonal guidance proteins in neurons and oligodendrocytes is associated with the neuropathology in CTE. Together, altered axonal guidance proteins may be potential pathological markers for CTE.
Lee, J,Hwang, Y J,Boo, J H,Han, D,Kwon, O K,Todorova, K,Kowall, N W,Kim, Y,Ryu, H Macmillan Publishers Limited 2011 Cell death and differentiation Vol.18 No.11
Huntington's disease (HD) is an autosomal-dominant neurological disorder caused by expanded CAG repeats in the Huntingtin (Htt) gene, but it is not known how this mutation causes neurodegeneration. Herein, we found that dysfunction of upstream binding factor-1 (UBF-1) is linked to reduced ribosomal DNA (rDNA) transcription in HD. We identified that UBF1 acetylation at Lys (K) 352 by CREB binding protein (CBP) is crucial for the transcriptional activity of rDNA. UBF1 mutation (K352A, K352Q, and K352R) decreased rDNA transcriptional activity. Moreover, both CBP–dHAT mutant and knockdown of CBP by siRNA reduced acetylation of UBF1 and resulted in the decreased transcription of rDNA into rRNA. ChIP analysis showed a significant reduction of UBF1 occupancy in the promoter of rDNA in STHdh<SUP>Q111</SUP> cell line model of HD. These results demonstrate that abnormal activity of UBF1 and its acetylation by CBP are linked to impaired rDNA transcription in HD. This novel mechanism suggests that modulation of UBF-mediated rDNA synthesis by CBP may be a therapeutic target for improving neuronal rDNA transcription in HD.
MST1 functions as a key modulator of neurodegeneration in a mouse model of ALS
Lee, Jae Keun,Shin, Jin Hee,Hwang, Sang Gil,Gwag, Byoung Joo,McKee, Ann C.,Lee, Junghee,Kowall, Neil W.,Ryu, Hoon,Lim, Dae-Sik,Choi, Eui-Ju National Academy of Sciences 2013 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.110 No.29
<P>Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by loss of motor neurons. Dominant mutations in the gene for superoxide dismutase 1 (SOD1) give rise to familial ALS by an unknown mechanism. Here we show that genetic deficiency of mammalian sterile 20-like kinase 1 (MST1) delays disease onset and extends survival in mice expressing the ALS-associated G93A mutant of human SOD1. SOD1(G93A) induces dissociation of MST1 from a redox protein thioredoxin-1 and promotes MST1 activation in spinal cord neurons in a reactive oxygen species–dependent manner. Moreover, MST1 was found to mediate SOD1(G93A)-induced activation of p38 mitogen-activated protein kinase and caspases as well as impairment of autophagy in spinal cord motoneurons of SOD1(G93A) mice. Our findings implicate MST1 as a key determinant of neurodegeneration in ALS.</P>