LIVIVO - The Search Portal for Life Sciences

zur deutschen Oberfläche wechseln
Advanced search

Search results

Result 1 - 10 of total 73

Search options

  1. Article ; Online: Insulin-Degrading Enzyme: Paradoxes and Possibilities.

    Leissring, Malcolm A

    Cells

    2021  Volume 10, Issue 9

    Abstract: More than seven decades have passed since the discovery of a proteolytic activity within crude tissue extracts that would become known as insulin-degrading enzyme (IDE). Certainly much has been learned about this atypical zinc-metallopeptidase; at the ... ...

    Abstract More than seven decades have passed since the discovery of a proteolytic activity within crude tissue extracts that would become known as insulin-degrading enzyme (IDE). Certainly much has been learned about this atypical zinc-metallopeptidase; at the same time, however, many quite fundamental gaps in our understanding remain. Herein, I outline what I consider to be among the most critical unresolved questions within the field, many presenting as intriguing paradoxes. For instance, where does IDE, a predominantly cytosolic protein with no signal peptide or clearly identified secretion mechanism, interact with insulin and other extracellular substrates? Where precisely is IDE localized within the cell, and what are its functional roles in these compartments? How does IDE, a bowl-shaped protein that completely encapsulates its substrates, manage to avoid getting "clogged" and thus rendered inactive virtually immediately? Although these paradoxes are by definition unresolved, I offer herein my personal insights and informed speculations based on two decades working on the biology and pharmacology of IDE and suggest specific experimental strategies for addressing these conundrums. I also offer what I believe to be especially fruitful avenues for investigation made possible by the development of new technologies and IDE-specific reagents. It is my hope that these thoughts will contribute to continued progress elucidating the physiology and pathophysiology of this important peptidase.
    MeSH term(s) Animals ; Humans ; Insulin/metabolism ; Insulysin/chemistry ; Insulysin/genetics ; Insulysin/metabolism
    Chemical Substances Insulin ; Insulysin (EC 3.4.24.56)
    Language English
    Publishing date 2021-09-16
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells10092445
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  2. Article ; Online: Insulin-Degrading Enzyme

    Malcolm A. Leissring

    Cells, Vol 10, Iss 2445, p

    Paradoxes and Possibilities

    2021  Volume 2445

    Abstract: More than seven decades have passed since the discovery of a proteolytic activity within crude tissue extracts that would become known as insulin-degrading enzyme (IDE). Certainly much has been learned about this atypical zinc-metallopeptidase; at the ... ...

    Abstract More than seven decades have passed since the discovery of a proteolytic activity within crude tissue extracts that would become known as insulin-degrading enzyme (IDE). Certainly much has been learned about this atypical zinc-metallopeptidase; at the same time, however, many quite fundamental gaps in our understanding remain. Herein, I outline what I consider to be among the most critical unresolved questions within the field, many presenting as intriguing paradoxes. For instance, where does IDE, a predominantly cytosolic protein with no signal peptide or clearly identified secretion mechanism, interact with insulin and other extracellular substrates? Where precisely is IDE localized within the cell, and what are its functional roles in these compartments? How does IDE, a bowl-shaped protein that completely encapsulates its substrates, manage to avoid getting “clogged” and thus rendered inactive virtually immediately? Although these paradoxes are by definition unresolved, I offer herein my personal insights and informed speculations based on two decades working on the biology and pharmacology of IDE and suggest specific experimental strategies for addressing these conundrums. I also offer what I believe to be especially fruitful avenues for investigation made possible by the development of new technologies and IDE-specific reagents. It is my hope that these thoughts will contribute to continued progress elucidating the physiology and pathophysiology of this important peptidase.
    Keywords diabetes mellitus ; insulin ; insulin-degrading enzyme ; proteolysis ; protease inhibitors ; Biology (General) ; QH301-705.5
    Subject code 571
    Language English
    Publishing date 2021-09-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

    More links

    Kategorien

    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

  3. Article ; Online: Cathepsin D: A Candidate Link between Amyloid β-protein and Tauopathy in Alzheimer Disease.

    Suire, Caitlin N / Leissring, Malcolm A

    Journal of experimental neurology

    2021  Volume 2, Issue 1, Page(s) 10–15

    Abstract: Alzheimer disease (AD) is a debilitating neurodegenerative disorder characterized by extracellular deposition of the amyloid β-protein (Aβ) and intraneuronal accumulation of the microtubule-associated protein, tau. Despite a wealth of experimental and ... ...

    Abstract Alzheimer disease (AD) is a debilitating neurodegenerative disorder characterized by extracellular deposition of the amyloid β-protein (Aβ) and intraneuronal accumulation of the microtubule-associated protein, tau. Despite a wealth of experimental and genetic evidence implicating both Aβ and tau in the pathogenesis of AD, the precise molecular links between these two pathological hallmarks have remained surprisingly elusive. Here, we review emerging evidence for a critical nexus among Aβ, tau, and the lysosomal protease cathepsin D (CatD) that we hypothesize may play a pivotal role in the etiology of AD. CatD degrades both Aβ and tau
    Language English
    Publishing date 2021-03-04
    Publishing country United States
    Document type Journal Article
    ISSN 2692-2819
    ISSN (online) 2692-2819
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

  4. Article ; Online: Aβ-Degrading Proteases: Therapeutic Potential in Alzheimer Disease.

    Leissring, Malcolm A

    CNS drugs

    2016  Volume 30, Issue 8, Page(s) 667–675

    Abstract: The amyloid β-protein (Aβ) plays an indispensable role in the pathogenesis of Alzheimer disease (AD). Aβ is subject to proteolytic degradation by a diverse array of peptidases and proteinases, known collectively as Aβ-degrading proteases (AβDPs). A ... ...

    Abstract The amyloid β-protein (Aβ) plays an indispensable role in the pathogenesis of Alzheimer disease (AD). Aβ is subject to proteolytic degradation by a diverse array of peptidases and proteinases, known collectively as Aβ-degrading proteases (AβDPs). A growing number of AβDPs have been identified that impact Aβ powerfully and in a surprising variety of ways. As such, AβDPs hold considerable therapeutic potential for the treatment and/or prevention of AD. Here, we critically review the relative merits of therapeutic strategies targeting AβDPs compared with current Aβ-lowering strategies focused on immunotherapies and pharmacological modulation of Aβ-producing enzymes. Several innovative advances have increased considerably the feasibility of delivering AβDPs to the brain or enhancing their activity in a non-invasive manner. We argue that therapies targeting AβDPs offer numerous potential advantages that should be explored through continued research into this promising field.
    MeSH term(s) Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Animals ; Brain/metabolism ; Humans ; Peptide Hydrolases/metabolism
    Chemical Substances Amyloid beta-Peptides ; Peptide Hydrolases (EC 3.4.-)
    Language English
    Publishing date 2016-07-21
    Publishing country New Zealand
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 1203800-3
    ISSN 1179-1934 ; 1172-7047
    ISSN (online) 1179-1934
    ISSN 1172-7047
    DOI 10.1007/s40263-016-0364-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

    Full text online

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 4083: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  5. Article: Aβ degradation-the inside story.

    Leissring, Malcolm A

    Frontiers in aging neuroscience

    2014  Volume 6, Page(s) 229

    Language English
    Publishing date 2014-08-26
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2558898-9
    ISSN 1663-4365
    ISSN 1663-4365
    DOI 10.3389/fnagi.2014.00229
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  6. Article ; Online: Quantitative, High-Throughput Assays for Proteolytic Degradation of Amylin.

    Suire, Caitlin N / Brizuela, Monica K / Leissring, Malcolm A

    Methods and protocols

    2020  Volume 3, Issue 4

    Abstract: Amylin is a pancreatic peptide hormone that regulates glucose homeostasis but also aggregates to form islet amyloid in type-2 diabetes. Given its role in both health and disease, there is renewed interest in proteolytic degradation of amylin by insulin- ... ...

    Abstract Amylin is a pancreatic peptide hormone that regulates glucose homeostasis but also aggregates to form islet amyloid in type-2 diabetes. Given its role in both health and disease, there is renewed interest in proteolytic degradation of amylin by insulin-degrading enzyme (IDE) and other proteases. Here, we describe the development and detailed characterization of three novel assays for amylin degradation, two based on a fluoresceinated and biotinylated form of rodent amylin (fluorescein-rodent amylin-biotin, FrAB), which can be used for any amylin protease, and another based on an internally quenched fluorogenic substrate (FRET-based amylin, FRAM), which is more specific for IDE. The FrAB-based substrate can be used in a readily implemented fluorescence-based protocol or in a fluorescence polarization (FP)-based protocol that is more amenable to high-throughput screening (HTS), whereas the FRAM substrate has the advantage of permitting continuous monitoring of proteolytic activity. All three assays yield highly quantitative data and are resistant to DMSO, and the FRAM and FP-based FrAB assay are ideally suited to HTS applications.
    Language English
    Publishing date 2020-11-24
    Publishing country Switzerland
    Document type Journal Article
    ISSN 2409-9279
    ISSN (online) 2409-9279
    DOI 10.3390/mps3040081
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

  7. Article ; Online: A Dual-Function "TRE-Lox" System for Genetic Deletion or Reversible, Titratable, and Near-Complete Downregulation of Cathepsin D.

    Terron, Heather M / Maranan, Derek S / Burgard, Luke A / LaFerla, Frank M / Lane, Shelley / Leissring, Malcolm A

    International journal of molecular sciences

    2023  Volume 24, Issue 7

    Abstract: Commonly employed methods for reversibly disrupting gene expression, such as those based on RNAi or CRISPRi, are rarely capable of achieving >80-90% downregulation, making them unsuitable for targeting genes that require more complete disruption to ... ...

    Abstract Commonly employed methods for reversibly disrupting gene expression, such as those based on RNAi or CRISPRi, are rarely capable of achieving >80-90% downregulation, making them unsuitable for targeting genes that require more complete disruption to elicit a phenotype. Genetic deletion, on the other hand, while enabling complete disruption of target genes, often produces undesirable irreversible consequences such as cytotoxicity or cell death. Here we describe the design, development, and detailed characterization of a dual-function "TRE-Lox" system for effecting either (a) doxycycline (Dox)-mediated downregulation or (b) genetic deletion of a target gene-the lysosomal aspartyl protease cathepsin D (CatD)-based on targeted insertion of a tetracycline-response element (TRE) and two LoxP sites into the 5' end of the endogenous CatD gene (
    MeSH term(s) Animals ; Mice ; Cathepsin D/genetics ; Cathepsin D/metabolism ; Down-Regulation/genetics ; Fibroblasts/metabolism ; Tetracycline ; Doxycycline/pharmacology ; Response Elements
    Chemical Substances Cathepsin D (EC 3.4.23.5) ; Tetracycline (F8VB5M810T) ; Doxycycline (N12000U13O)
    Language English
    Publishing date 2023-04-04
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms24076745
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  8. Article ; Online: Prominent tauopathy and intracellular β-amyloid accumulation triggered by genetic deletion of cathepsin D: implications for Alzheimer disease pathogenesis.

    Terron, Heather M / Parikh, Sagar J / Abdul-Hay, Samer O / Sahara, Tomoko / Kang, Dongcheul / Dickson, Dennis W / Saftig, Paul / LaFerla, Frank M / Lane, Shelley / Leissring, Malcolm A

    Alzheimer's research & therapy

    2024  Volume 16, Issue 1, Page(s) 70

    Abstract: Background: Cathepsin D (CatD) is a lysosomal protease that degrades both the amyloid-β protein (Aβ) and the microtubule-associated protein, tau, which accumulate pathognomonically in Alzheimer disease (AD), but few studies have examined the role of ... ...

    Abstract Background: Cathepsin D (CatD) is a lysosomal protease that degrades both the amyloid-β protein (Aβ) and the microtubule-associated protein, tau, which accumulate pathognomonically in Alzheimer disease (AD), but few studies have examined the role of CatD in the development of Aβ pathology and tauopathy in vivo.
    Methods: CatD knockout (KO) mice were crossed to human amyloid precursor protein (hAPP) transgenic mice, and amyloid burden was quantified by ELISA and immunohistochemistry (IHC). Tauopathy in CatD-KO mice, as initially suggested by Gallyas silver staining, was further characterized by extensive IHC and biochemical analyses. Controls included human tau transgenic mice (JNPL3) and another mouse model of a disease (Krabbe A) characterized by pronounced lysosomal dysfunction. Additional experiments examined the effects of CatD inhibition on tau catabolism in vitro and in cultured neuroblastoma cells with inducible expression of human tau.
    Results: Deletion of CatD in hAPP transgenic mice triggers large increases in cerebral Aβ, manifesting as intense, exclusively intracellular aggregates; extracellular Aβ deposition, by contrast, is neither triggered by CatD deletion, nor affected in older, haploinsufficient mice. Unexpectedly, CatD-KO mice were found to develop prominent tauopathy by just ∼ 3 weeks of age, accumulating sarkosyl-insoluble, hyperphosphorylated tau exceeding the pathology present in aged JNPL3 mice. CatD-KO mice exhibit pronounced perinuclear Gallyas silver staining reminiscent of mature neurofibrillary tangles in human AD, together with widespread phospho-tau immunoreactivity. Striking increases in sarkosyl-insoluble phospho-tau (∼ 1250%) are present in CatD-KO mice but notably absent from Krabbe A mice collected at an identical antemortem interval. In vitro and in cultured cells, we show that tau catabolism is slowed by blockade of CatD proteolytic activity, including via competitive inhibition by Aβ42.
    Conclusions: Our findings support a major role for CatD in the proteostasis of both Aβ and tau in vivo. To our knowledge, the CatD-KO mouse line is the only model to develop detectable Aβ accumulation and profound tauopathy in the absence of overexpression of hAPP or human tau with disease-associated mutations. Given that tauopathy emerges from disruption of CatD, which can itself be potently inhibited by Aβ42, our findings suggest that impaired CatD activity may represent a key mechanism linking amyloid accumulation and tauopathy in AD.
    MeSH term(s) Aged ; Animals ; Humans ; Mice ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/metabolism ; Cathepsin D ; Disease Models, Animal ; Mice, Knockout ; Mice, Transgenic ; tau Proteins/genetics ; tau Proteins/metabolism ; Tauopathies/genetics ; Tauopathies/metabolism
    Chemical Substances Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Cathepsin D (EC 3.4.23.5) ; tau Proteins ; Ctsd protein, mouse (EC 3.4.23.5)
    Language English
    Publishing date 2024-04-04
    Publishing country England
    Document type Journal Article
    ZDB-ID 2506521-X
    ISSN 1758-9193 ; 1758-9193
    ISSN (online) 1758-9193
    ISSN 1758-9193
    DOI 10.1186/s13195-024-01443-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  9. Article ; Online: Targeting Insulin-Degrading Enzyme in Insulin Clearance.

    Leissring, Malcolm A / González-Casimiro, Carlos M / Merino, Beatriz / Suire, Caitlin N / Perdomo, Germán

    International journal of molecular sciences

    2021  Volume 22, Issue 5

    Abstract: Hepatic insulin clearance, a physiological process that in response to nutritional cues clears ~50-80% of circulating insulin, is emerging as an important factor in our understanding of the pathogenesis of type 2 diabetes mellitus (T2DM). Insulin- ... ...

    Abstract Hepatic insulin clearance, a physiological process that in response to nutritional cues clears ~50-80% of circulating insulin, is emerging as an important factor in our understanding of the pathogenesis of type 2 diabetes mellitus (T2DM). Insulin-degrading enzyme (IDE) is a highly conserved Zn
    MeSH term(s) Animals ; Diabetes Mellitus, Type 2/drug therapy ; Diabetes Mellitus, Type 2/enzymology ; Enzyme Inhibitors/therapeutic use ; Humans ; Insulin/metabolism ; Insulysin/antagonists & inhibitors
    Chemical Substances Enzyme Inhibitors ; Insulin ; Insulysin (EC 3.4.24.56)
    Language English
    Publishing date 2021-02-24
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms22052235
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  10. Article ; Online: Correction to: Insulin-degrading enzyme ablation in mouse pancreatic alpha cells triggers cell proliferation, hyperplasia and glucagon secretion dysregulation.

    Merino, Beatriz / Casanueva-Álvarez, Elena / Quesada, Iván / González-Casimiro, Carlos M / Fernández-Díaz, Cristina M / Postigo-Casado, Tamara / Leissring, Malcolm A / Kaestner, Klaus H / Perdomo, Germán / Cózar-Castellano, Irene

    Diabetologia

    2023  Volume 67, Issue 1, Page(s) 218–219

    Language English
    Publishing date 2023-11-15
    Publishing country Germany
    Document type Published Erratum
    ZDB-ID 1694-9
    ISSN 1432-0428 ; 0012-186X
    ISSN (online) 1432-0428
    ISSN 0012-186X
    DOI 10.1007/s00125-023-06037-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 279: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

To top