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Article ; Online: Feasibility and considerations of epsin2 as a candidate target for multiple system atrophy treatment.

Cheng, An / Cai, Bo / Fukunaga, Kohji / Sasaki, Takuya / Lakkaraju, Aparna

2023 Volume 27, Issue 11, Page(s) 1031–1034

MeSH term(s)	Humans ; Multiple System Atrophy/drug therapy ; Feasibility Studies ; alpha-Synuclein/metabolism ; Brain/metabolism
Chemical Substances	alpha-Synuclein
Language	English
Publishing date	2023-12-07
Publishing country	England
Document type	Editorial ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2055208-7
ISSN	1744-7631 ; 1472-8222
ISSN (online)	1744-7631
ISSN	1472-8222
DOI	10.1080/14728222.2023.2277227
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Article: Analysis of mitochondrial dynamics and function in the retinal pigment epithelium by high-speed high-resolution live imaging.

Tan, Li Xuan / Li, Jianlong / Germer, Colin J / Lakkaraju, Aparna

Frontiers in cell and developmental biology

2022 Volume 10, Page(s) 1044672

Abstract: Mitochondrial dysfunction is strongly implicated in neurodegenerative diseases including age-related macular degeneration (AMD), which causes irreversible blindness in over 50 million older adults worldwide. A key site of insult in AMD is the retinal ... ...

Abstract	Mitochondrial dysfunction is strongly implicated in neurodegenerative diseases including age-related macular degeneration (AMD), which causes irreversible blindness in over 50 million older adults worldwide. A key site of insult in AMD is the retinal pigment epithelium (RPE), a monolayer of postmitotic polarized cells that performs essential functions for photoreceptor health and vision. Recent studies from our group and others have identified several features of mitochondrial dysfunction in AMD including mitochondrial fragmentation and bioenergetic defects. While these studies provide valuable insight at fixed points in time, high-resolution, high-speed live imaging is essential for following mitochondrial injury in real time and identifying disease mechanisms. Here, we demonstrate the advantages of live imaging to investigate RPE mitochondrial dynamics in cell-based and mouse models. We show that mitochondria in the RPE form extensive networks that are destroyed by fixation and discuss important live imaging considerations that can interfere with accurate evaluation of mitochondrial integrity such as RPE differentiation status and acquisition parameters. Our data demonstrate that RPE mitochondria show localized heterogeneities in membrane potential and ATP production that could reflect focal changes in metabolism and oxidative stress. Contacts between the mitochondria and organelles such as the ER and lysosomes mediate calcium flux and mitochondrial fission. Live imaging of mouse RPE flatmounts revealed a striking loss of mitochondrial integrity in albino mouse RPE compared to pigmented mice that could have significant functional consequences for cellular metabolism. Our studies lay a framework to guide experimental design and selection of model systems for evaluating mitochondrial health and function in the RPE.
Language	English
Publishing date	2022-10-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2022.1044672
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Article ; Online: Optineurin tunes outside-in signaling to regulate lysosome biogenesis and phagocytic clearance in the retina.

Tan, Li Xuan / Germer, Colin J / Thamban, Thushara / La Cunza, Nilsa / Lakkaraju, Aparna

Current biology : CB

2023 Volume 33, Issue 18, Page(s) 3805–3820.e7

Abstract: Balancing the competing demands of phagolysosomal degradation and autophagy is a significant challenge for phagocytic tissues. Yet how this plasticity is accomplished in health and disease is poorly understood. In the retina, circadian phagocytosis and ... ...

Abstract	Balancing the competing demands of phagolysosomal degradation and autophagy is a significant challenge for phagocytic tissues. Yet how this plasticity is accomplished in health and disease is poorly understood. In the retina, circadian phagocytosis and degradation of photoreceptor outer segments by the postmitotic retinal pigment epithelium (RPE) are essential for healthy vision. Disrupted autophagy due to mechanistic target of rapamycin (mTOR) overactivation in the RPE is associated with blinding macular degenerations; however, outer segment degradation is unaffected in these diseases, indicating that distinct mechanisms regulate these clearance mechanisms. Here, using advanced imaging and mouse models, we identify optineurin as a key regulator that tunes phagocytosis and lysosomal capacity to meet circadian demands and helps prioritize outer segment clearance by the RPE in macular degenerations. High-resolution live-cell imaging implicates optineurin in scissioning outer segment tips prior to engulfment, analogous to microglial trogocytosis of neuronal processes. Optineurin is essential for recruiting light chain 3 (LC3), which anchors outer segment phagosomes to microtubules and facilitates phagosome maturation and fusion with lysosomes. This dynamically activates transcription factor EB (TFEB) to induce lysosome biogenesis in an mTOR-independent, transient receptor potential-mucolipin 1 (TRPML1)-dependent manner. RNA-seq analyses show that expression of TFEB target genes temporally tracks with optineurin recruitment and that lysosomal and autophagy genes are controlled by distinct transcriptional programs in the RPE. The unconventional plasma membrane-to-nucleus signaling mediated by optineurin ensures outer segment degradation under conditions of impaired autophagy in macular degeneration models. Independent regulation of these critical clearance mechanisms would help safeguard the metabolic fitness of the RPE throughout the organismal lifespan.
MeSH term(s)	Mice ; Animals ; Lysosomes/metabolism ; Phagocytosis ; Retinal Pigment Epithelium/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Macular Degeneration/metabolism
Chemical Substances	TOR Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2023-08-15
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2023.07.031
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Article: Endo-lysosome function in the retinal pigment epithelium in health and disease.

Lakkaraju, Aparna

Advances in experimental medicine and biology

2012 Volume 723, Page(s) 723–729

MeSH term(s)	Endosomes/physiology ; Humans ; Lysosomes/physiology ; Retinal Diseases/pathology ; Retinal Diseases/physiopathology ; Retinal Pigment Epithelium/cytology ; Retinal Pigment Epithelium/physiology
Language	English
Publishing date	2012
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-1-4614-0631-0_92
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Article: Early Endosome Morphology in Health and Disease.

Kaur, Gulpreet / Lakkaraju, Aparna

Advances in experimental medicine and biology

2018 Volume 1074, Page(s) 335–343

Abstract: Early endosomes are organelles that receive macromolecules and solutes from the extracellular environment. The major function of early endosomes is to sort these cargos into recycling and degradative compartments of the cell. Degradation of the cargo ... ...

Abstract	Early endosomes are organelles that receive macromolecules and solutes from the extracellular environment. The major function of early endosomes is to sort these cargos into recycling and degradative compartments of the cell. Degradation of the cargo involves maturation of early endosomes into late endosomes, which, after acquisition of hydrolytic enzymes, form lysosomes. Endosome maturation involves recruitment of specific proteins and lipids to the early endosomal membrane, which drives changes in endosome morphology. Defects in early endosome maturation are generally accompanied by alterations in morphology, such as increase in volume and/or number. Enlarged early endosomes have been observed in Alzheimer's disease and Niemann Pick Disease type C, which also exhibit defects in endocytic sorting. This article discusses the mechanisms that regulate early endosome morphology and highlights the potential importance of endosome maturation in the retinal pigment epithelium.
MeSH term(s)	Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Animals ; Disease Models, Animal ; Down Syndrome/metabolism ; Down Syndrome/pathology ; Endocytosis/physiology ; Endosomes/physiology ; Endosomes/ultrastructure ; Humans ; Macular Degeneration/congenital ; Macular Degeneration/metabolism ; Macular Degeneration/pathology ; Membrane Fusion ; Membrane Lipids/metabolism ; Membrane Proteins/metabolism ; Mice ; Microtubules/metabolism ; Microtubules/ultrastructure ; Models, Biological ; Niemann-Pick Disease, Type C/metabolism ; Niemann-Pick Disease, Type C/pathology ; Organelle Biogenesis ; Protein Transport/physiology ; rab GTP-Binding Proteins/metabolism
Chemical Substances	Membrane Lipids ; Membrane Proteins ; rab GTP-Binding Proteins (EC 3.6.5.2)
Language	English
Publishing date	2018-05-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-319-75402-4_41
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Article ; Online: Does senescence play a role in age-related macular degeneration?

Malek, Goldis / Campisi, Judith / Kitazawa, Koji / Webster, Corey / Lakkaraju, Aparna / Skowronska-Krawczyk, Dorota

Experimental eye research

2022 Volume 225, Page(s) 109254

Abstract: Advanced age is the most established risk factor for developing age-related macular degeneration (AMD), one of the leading causes of visual impairment in the elderly, in Western and developed countries. Similarly, after middle age, there is an ... ...

Abstract	Advanced age is the most established risk factor for developing age-related macular degeneration (AMD), one of the leading causes of visual impairment in the elderly, in Western and developed countries. Similarly, after middle age, there is an exponential increase in pathologic molecular and cellular events that can induce senescence, traditionally defined as an irreversible loss of the cells' ability to divide and most recently reported to also occur in select post-mitotic and terminally differentiated cells, such as neurons. Together these facts raise the question as to whether or not cellular senescence, may play a role in the development of AMD. A number of studies have reported the effect of ocular-relevant inducers of senescence using primarily in vitro models of poorly polarized, actively dividing retinal pigment epithelial (RPE) cell lines. However, in interpretating the data, the fidelity of these culture models to the RPE in vivo, must be considered. Fewer studies have explored the presence and/or impact of senescent cells in in vivo models that present with phenotypic features of AMD, leaving this an open field for further investigation. The goal of this review is to discuss current thoughts on the potential role of senescence in AMD development and progression, with consideration of the model systems used and their relevance to human disease.
MeSH term(s)	Middle Aged ; Humans ; Aged ; Retinal Pigment Epithelium/metabolism ; Macular Degeneration/metabolism ; Cellular Senescence
Language	English
Publishing date	2022-09-21
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80122-7
ISSN	1096-0007 ; 0014-4835
ISSN (online)	1096-0007
ISSN	0014-4835
DOI	10.1016/j.exer.2022.109254
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Zs.A 163: Show issues

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ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Complement activation, lipid metabolism, and mitochondrial injury: Converging pathways in age-related macular degeneration.

Tan, Li Xuan / Germer, Colin J / La Cunza, Nilsa / Lakkaraju, Aparna

Redox biology

2020 Volume 37, Page(s) 101781

Abstract: The retinal pigment epithelium (RPE) is the primary site of injury in non-neovascular age-related macular degeneration or dry AMD. Polymorphisms in genes that regulate complement activation and cholesterol metabolism are strongly associated with AMD, but ...

Abstract	The retinal pigment epithelium (RPE) is the primary site of injury in non-neovascular age-related macular degeneration or dry AMD. Polymorphisms in genes that regulate complement activation and cholesterol metabolism are strongly associated with AMD, but the biology underlying disease-associated variants is not well understood. Here, we highlight recent studies that have used molecular, biochemical, and live-cell imaging methods to elucidate mechanisms by which aging-associated insults conspire with AMD genetic risk variants to tip the balance towards disease. We discuss how critical functions including lipid metabolism, autophagy, complement regulation, and mitochondrial dynamics are compromised in the RPE, and how a deeper understanding of these mechanisms has helped identify promising therapeutic targets to preserve RPE homeostasis in AMD.
MeSH term(s)	Complement Activation/genetics ; Humans ; Lipid Metabolism/genetics ; Macular Degeneration/genetics ; Macular Degeneration/metabolism ; Mitochondria/genetics ; Mitochondria/metabolism ; Retinal Pigment Epithelium/metabolism
Language	English
Publishing date	2020-11-02
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2701011-9
ISSN	2213-2317 ; 2213-2317
ISSN (online)	2213-2317
ISSN	2213-2317
DOI	10.1016/j.redox.2020.101781
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Article ; Online: Endoplasmic reticulum acetyltransferases Atase1 and Atase2 differentially regulate reticulophagy, macroautophagy and cellular acetyl-CoA metabolism.

Rigby, Michael J / Lawton, Alexis J / Kaur, Gulpreet / Banduseela, Varuna C / Kamm, William E / Lakkaraju, Aparna / Denu, John M / Puglielli, Luigi

Communications biology

2021 Volume 4, Issue 1, Page(s) 454

Abstract: ... ...

Abstract	N
MeSH term(s)	Acetyl Coenzyme A/metabolism ; Acetyltransferases/genetics ; Acetyltransferases/metabolism ; Animals ; Autophagy/genetics ; Endoplasmic Reticulum/physiology ; Female ; Macroautophagy/genetics ; Male ; Mice ; Mice, Knockout
Chemical Substances	Acetyl Coenzyme A (72-89-9) ; Acetyltransferases (EC 2.3.1.-)
Language	English
Publishing date	2021-04-12
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-021-01992-8
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Article ; Online: Mitochondria-dependent phase separation of disease-relevant proteins drives pathological features of age-related macular degeneration.

La Cunza, Nilsa / Tan, Li Xuan / Thamban, Thushara / Germer, Colin J / Rathnasamy, Gurugirijha / Toops, Kimberly A / Lakkaraju, Aparna

JCI insight

2021 Volume 6, Issue 9

Abstract: Age-related macular degeneration (AMD) damages the retinal pigment epithelium (RPE), the tissue that safeguards photoreceptor health, leading to irreversible vision loss. Polymorphisms in cholesterol and complement genes are implicated in AMD, yet ... ...

Abstract	Age-related macular degeneration (AMD) damages the retinal pigment epithelium (RPE), the tissue that safeguards photoreceptor health, leading to irreversible vision loss. Polymorphisms in cholesterol and complement genes are implicated in AMD, yet mechanisms linking risk variants to RPE injury remain unclear. We sought to determine how allelic variants in the apolipoprotein E cholesterol transporter modulate RPE homeostasis and function. Using live-cell imaging, we show that inefficient cholesterol transport by the AMD risk-associated ApoE2 increases RPE ceramide, leading to autophagic defects and complement-mediated mitochondrial damage. Mitochondrial injury drives redox state-sensitive cysteine-mediated phase separation of ApoE2, forming biomolecular condensates that could nucleate drusen. The protective ApoE4 isoform lacks these cysteines and is resistant to phase separation and condensate formation. In Abca-/- Stargardt macular degeneration mice, mitochondrial dysfunction induces liquid-liquid phase separation of p62/SQSTM1, a multifunctional protein that regulates autophagy. Drugs that decrease RPE cholesterol or ceramide prevent mitochondrial injury and phase separation in vitro and in vivo. In AMD donor RPE, mitochondrial fragmentation correlates with ApoE and p62 condensates. Our studies demonstrate that major AMD genetic and biological risk pathways converge upon RPE mitochondria, and identify mitochondrial stress-mediated protein phase separation as an important pathogenic mechanism and promising therapeutic target in AMD.
MeSH term(s)	Animals ; Apolipoprotein E2/genetics ; Apolipoprotein E4/genetics ; Autophagy/physiology ; Biomolecular Condensates/metabolism ; Biomolecular Condensates/pathology ; Ceramides/metabolism ; Cholesterol/metabolism ; Complement System Proteins/metabolism ; Intravital Microscopy ; Macular Degeneration/genetics ; Macular Degeneration/metabolism ; Macular Degeneration/pathology ; Mice ; Mice, Knockout ; Mitochondria/metabolism ; Mitochondria/pathology ; Oxidative Stress ; Retinal Pigment Epithelium/metabolism ; Retinal Pigment Epithelium/pathology ; Sequestosome-1 Protein/metabolism
Chemical Substances	Apolipoprotein E2 ; Apolipoprotein E4 ; Ceramides ; Sequestosome-1 Protein ; Sqstm1 protein, mouse ; Complement System Proteins (9007-36-7) ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2021-05-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.142254
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Article: Let's play a game of chutes and ladders: Lysosome fusion with the epithelial plasma membrane.

Toops, Kimberly A / Lakkaraju, Aparna

Communicative & integrative biology

2013 Volume 6, Issue 4, Page(s) e24474

Abstract: In non-polarized cells, calcium-induced exocytosis of "conventional" lysosomes is important in diverse processes like membrane repair after exposure to pore-forming toxins and clearance of cellular debris. Resealing of torn membranes is especially ... ...

Abstract	In non-polarized cells, calcium-induced exocytosis of "conventional" lysosomes is important in diverse processes like membrane repair after exposure to pore-forming toxins and clearance of cellular debris. Resealing of torn membranes is especially critical for barrier epithelia that directly interact with pathogens and toxins, which can result in membrane microdisruptions and lesions. However, whether lysosomes participate in membrane repair in polarized epithelia has been an open question. We recently reported that in polarized Madin-Darby canine kidney (MDCK) cells, localized influx of calcium induces lysosomes to fuse with the basolateral membrane. This spatial segregation of exocytosis depends on an intact actin cytoskeleton, membrane cholesterol and restricted distribution of fusion machinery such as the t-SNARE syntaxin 4. Our data show that the polarity of syntaxin 4 (which is regulated by the clathrin adaptor protein AP-1) dictates whether lysosomes parachute down to the basolateral membrane or take a ladder up to the apical membrane. Here, we speculate about additional machinery (such as the lysosomal calcium sensor synaptotagmin VII and the v-SNARE VAMP7) that could be involved in polarized fusion of lysosomes with the epithelial membrane. We also discuss the potential importance of lysosome exocytosis in maintaining membrane integrity in the retinal pigment epithelium, the primary tissue affected in blinding diseases such as age-related macular degeneration.
Language	English
Publishing date	2013-05-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2451097-X
ISSN	1942-0889
ISSN	1942-0889
DOI	10.4161/cib.24474
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