LIVIVO - The Search Portal for Life Sciences

zur deutschen Oberfläche wechseln
Advanced search

Search results

Result 1 - 10 of total 41

Search options

  1. Article ; Online: Calculating Sample Size Requirements for Temporal Dynamics in Single-Cell Proteomics.

    Boekweg, Hannah / Guise, Amanda J / Plowey, Edward D / Kelly, Ryan T / Payne, Samuel H

    Molecular & cellular proteomics : MCP

    2021  Volume 20, Page(s) 100085

    Abstract: Single-cell measurements are uniquely capable of characterizing cell-to-cell heterogeneity and have been used to explore the large diversity of cell types and physiological functions present in tissues and other complex cell assemblies. An intriguing ... ...

    Abstract Single-cell measurements are uniquely capable of characterizing cell-to-cell heterogeneity and have been used to explore the large diversity of cell types and physiological functions present in tissues and other complex cell assemblies. An intriguing application of single-cell proteomics is the characterization of proteome dynamics during biological transitions, like cellular differentiation or disease progression. Time-course experiments, which regularly take measurements during state transitions, rely on the ability to detect dynamic trajectories in a data series. However, in a single-cell proteomics experiment, cell-to-cell heterogeneity complicates the confident identification of proteome dynamics as measurement variability may be higher than expected. Therefore, a critical question for these experiments is how many data points need to be acquired during the time course to enable robust statistical analysis. We present here an analysis of the most important variables that affect statistical confidence in the detection of proteome dynamics: fold change, measurement variability, and the number of cells measured during the time course. Importantly, we show that datasets with less than 16 measurements across the time domain suffer from low accuracy and also have a high false-positive rate. We also demonstrate how to balance competing demands in experimental design to achieve a desired result.
    MeSH term(s) Animals ; Cell Line ; Mice ; Proteomics/methods ; Sample Size ; Single-Cell Analysis
    Language English
    Publishing date 2021-04-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2075924-1
    ISSN 1535-9484 ; 1535-9476
    ISSN (online) 1535-9484
    ISSN 1535-9476
    DOI 10.1016/j.mcpro.2021.100085
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  2. Article ; Online: Hippocampal phospho-tau/MAPT neuropathology in the fornix in Alzheimer disease: an immunohistochemical autopsy study.

    Plowey, Edward D / Ziskin, Jennifer L

    Acta neuropathologica communications

    2016  Volume 4, Issue 1, Page(s) 114

    Abstract: Whereas early Alzheimer disease (AD) neuropathology and mild cognitive impairment are relatively common in aging, accurate prediction of patients that will progress to dementia requires new biomarkers. Recently, substantial work has focused on phospho- ... ...

    Abstract Whereas early Alzheimer disease (AD) neuropathology and mild cognitive impairment are relatively common in aging, accurate prediction of patients that will progress to dementia requires new biomarkers. Recently, substantial work has focused on phospho-tau/MAPT (p-MAPT) neuropathology since its regional propagation correlates with the degree of cognitive impairment in AD. Recent diffusion tensor imaging studies in AD suggest that increased diffusion in the fornix secondary to p-MAPT-related axonal injury could serve as a predictive biomarker of the risk of disease progression. However, our knowledge of p-MAPT neuropathology in the fornix is limited. To address this gap in knowledge, we examined p-MAPT neuropathology in the fornix and basal forebrain nuclei via AT8 immunohistochemistry in 39 brain autopsies spanning the spectrum of AD neuropathologic changes. We found that the fornix and its precommissural efferent target nuclei (septum and nucleus accumbens) demonstrated neuronal and thread-like p-MAPT neuropathology only in National Institute on Aging/Alzheimer Association (NIA/AA) stages B2 and B3 of neurofibrillary degeneration, consistent with involvement after (and propagation from) the hippocampal formation. Interestingly, although tau astrogliopathy was frequently observed in the mammillary bodies in stage B2, neuronal tauopathy was not observed in the postcommissural targets (mammillary bodies and anterior thalamic nucleus) until stage B3. Tauopathy in the nucleus basalis of Meynert was strongly correlated with p-MAPT-positive axons in the fornix, suggesting that projections to the hippocampus also likely contribute to fornix tauopathy. Our cross-sectional autopsy findings indicate that the fornix is involved by p-MAPT neuropathology secondary to hippocampal involvement by AD neuropathology. Furthermore, our findings are compatible with the goal of in vivo detection of p-MAPT-related axonal pathology in the fornix in AD as a possible biomarker of p-MAPT progression from the hippocampal formation and underscore a need for additional clinical-radiologic-pathologic correlation studies.
    MeSH term(s) Aged ; Aged, 80 and over ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Autopsy ; Female ; Fornix, Brain/metabolism ; Fornix, Brain/pathology ; Humans ; Male ; Middle Aged ; Nerve Degeneration/metabolism ; Nerve Degeneration/pathology ; Neurofibrillary Tangles/metabolism ; Neurofibrillary Tangles/pathology ; Phosphorylation ; tau Proteins/metabolism
    Chemical Substances MAPT protein, human ; tau Proteins
    Language English
    Publishing date 2016-10-28
    Publishing country England
    Document type Journal Article
    ZDB-ID 2715589-4
    ISSN 2051-5960 ; 2051-5960
    ISSN (online) 2051-5960
    ISSN 2051-5960
    DOI 10.1186/s40478-016-0388-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  3. Article ; Online: TDP-43-stratified single-cell proteomics of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosis.

    Guise, Amanda J / Misal, Santosh A / Carson, Richard / Chu, Jen-Hwa / Boekweg, Hannah / Van Der Watt, Daisha / Welsh, Nora C / Truong, Thy / Liang, Yiran / Xu, Shanqin / Benedetto, Gina / Gagnon, Jake / Payne, Samuel H / Plowey, Edward D / Kelly, Ryan T

    Cell reports

    2024  Volume 43, Issue 1, Page(s) 113636

    Abstract: A limitation of conventional bulk-tissue proteome studies in amyotrophic lateral sclerosis (ALS) is the confounding of motor neuron (MN) signals by admixed non-MN proteins. Here, we leverage laser capture microdissection and nanoPOTS single-cell mass ... ...

    Abstract A limitation of conventional bulk-tissue proteome studies in amyotrophic lateral sclerosis (ALS) is the confounding of motor neuron (MN) signals by admixed non-MN proteins. Here, we leverage laser capture microdissection and nanoPOTS single-cell mass spectrometry-based proteomics to query changes in protein expression in single MNs from postmortem ALS and control tissues. In a follow-up analysis, we examine the impact of stratification of MNs based on cytoplasmic transactive response DNA-binding protein 43 (TDP-43)+ inclusion pathology on the profiles of 2,238 proteins. We report extensive overlap in differentially abundant proteins identified in ALS MNs with or without overt TDP-43 pathology, suggesting early and sustained dysregulation of cellular respiration, mRNA splicing, translation, and vesicular transport in ALS. Together, these data provide insights into proteome-level changes associated with TDP-43 proteinopathy and begin to demonstrate the utility of pathology-stratified trace sample proteomics for understanding single-cell protein dynamics in human neurologic diseases.
    MeSH term(s) Humans ; Amyotrophic Lateral Sclerosis/genetics ; DNA-Binding Proteins/metabolism ; Motor Neurons/metabolism ; Proteome/metabolism ; Proteomics
    Chemical Substances DNA-Binding Proteins ; Proteome ; TARDBP protein, human
    Language English
    Publishing date 2024-01-05
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2023.113636
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  4. Article ; Online: Histologic Artifacts of Autolytic Müller Cell Foot Process Swelling in Postmortem Examination of Infant Eyes: Potential Pitfall in the Evaluation of Traumatic Retinal Hemorrhages.

    Plowey, Edward D / Egbert, Peter R

    JAMA ophthalmology

    2015  Volume 133, Issue 6, Page(s) 706–709

    Abstract: Importance: Retinal hemorrhages are an important sequela of fatal head trauma. The accurate pathologic diagnosis of retinal hemorrhages has critical implications for determination of the manner of death.: Observations: We describe an autolytic ... ...

    Abstract Importance: Retinal hemorrhages are an important sequela of fatal head trauma. The accurate pathologic diagnosis of retinal hemorrhages has critical implications for determination of the manner of death.
    Observations: We describe an autolytic postmortem histologic artifact of eosinophilic Müller cell foot process swelling that mimics a nerve fiber layer hemorrhage. From April 24, 2012, through November 11, 2014, we conducted postmortem examination of the eyes of 23 infants and children who were referred to our institution for possible nonaccidental head trauma. A focal artifact of Müller cell foot process swelling was identified in most patients (16 of 23) up to 4 years of age. Three infants, all of whom were younger than 3 months, demonstrated diffusely swollen Müller cell foot processes with intensely eosinophilic cytoplasm that mimicked erythrocytes of nerve fiber layer hemorrhages. The difference in the mean age between patients with diffuse eosinophilic artifacts (1.7 months) and patients with only a multifocal, focal, or absent artifact (13.3 months) was 11.6 months (95% CI, 6.5-16.7 months). Glycophorin C immunohistochemical analysis was useful to differentiate this artifact from nerve fiber layer hemorrhage.
    Conclusions and relevance: Our case review demonstrates an artifact of eosinophilic Müller cell foot processes swelling in postmortem examination of young infant eyes, a potential pitfall in the diagnosis of retinal hemorrhages. Our findings have important implications for the diagnosis of retinal hemorrhages in potential cases of nonaccidental head injury.
    MeSH term(s) Artifacts ; Autolysis ; Autopsy ; Battered Child Syndrome/diagnosis ; Child, Preschool ; Craniocerebral Trauma/diagnosis ; Ependymoglial Cells/metabolism ; Ependymoglial Cells/pathology ; Female ; Glycophorin/metabolism ; Humans ; Immunohistochemistry ; Infant ; Male ; Retinal Hemorrhage/diagnosis ; Retinal Hemorrhage/metabolism
    Chemical Substances Glycophorin
    Language English
    Publishing date 2015-06
    Publishing country United States
    Document type Case Reports ; Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2701705-9
    ISSN 2168-6173 ; 2168-6165
    ISSN (online) 2168-6173
    ISSN 2168-6165
    DOI 10.1001/jamaophthalmol.2015.0493
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  5. Article: TDP-43-stratified single-cell proteomic profiling of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosis.

    Guise, Amanda J / Misal, Santosh A / Carson, Richard / Boekweg, Hannah / Watt, Daisha Van Der / Truong, Thy / Liang, Yiran / Chu, Jen-Hwa / Welsh, Nora C / Gagnon, Jake / Payne, Samuel H / Plowey, Edward D / Kelly, Ryan T

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Unbiased proteomics has been employed to interrogate central nervous system (CNS) tissues (brain, spinal cord) and fluid matrices (CSF, plasma) from amyotrophic lateral sclerosis (ALS) patients; yet, a limitation of conventional bulk tissue studies is ... ...

    Abstract Unbiased proteomics has been employed to interrogate central nervous system (CNS) tissues (brain, spinal cord) and fluid matrices (CSF, plasma) from amyotrophic lateral sclerosis (ALS) patients; yet, a limitation of conventional bulk tissue studies is that motor neuron (MN) proteome signals may be confounded by admixed non-MN proteins. Recent advances in trace sample proteomics have enabled quantitative protein abundance datasets from single human MNs (Cong et al., 2020b). In this study, we leveraged laser capture microdissection (LCM) and nanoPOTS (Zhu et al., 2018c) single-cell mass spectrometry (MS)-based proteomics to query changes in protein expression in single MNs from postmortem ALS and control donor spinal cord tissues, leading to the identification of 2515 proteins across MNs samples (>900 per single MN) and quantitative comparison of 1870 proteins between disease groups. Furthermore, we studied the impact of enriching/stratifying MN proteome samples based on the presence and extent of immunoreactive, cytoplasmic TDP-43 inclusions, allowing identification of 3368 proteins across MNs samples and profiling of 2238 proteins across TDP-43 strata. We found extensive overlap in differential protein abundance profiles between MNs with or without obvious TDP-43 cytoplasmic inclusions that together point to early and sustained dysregulation of oxidative phosphorylation, mRNA splicing and translation, and retromer-mediated vesicular transport in ALS. Our data are the first unbiased quantification of single MN protein abundance changes associated with TDP-43 proteinopathy and begin to demonstrate the utility of pathology-stratified trace sample proteomics for understanding single-cell protein abundance changes in human neurologic diseases.
    Language English
    Publishing date 2023-06-10
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.06.08.544233
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  6. Article ; Online: TBL1XR1

    Jangam, Diwash / Sridhar, Kaushik / Butzmann, Alexandra / Samghabadi, Peyman / Plowey, Edward D / Ohgami, Robert S

    Current eye research

    2020  Volume 45, Issue 12, Page(s) 1583–1589

    Abstract: Purpose: Extranodal marginal zone B-cell lymphoma (EMZL) of mucosa-associated lymphoid tissue (MALT) that affects the ocular adnexa, also known as ocular adnexal MALT lymphomas (OAML), are low-grade lymphomas that mostly affect elderly individuals. This ...

    Abstract Purpose: Extranodal marginal zone B-cell lymphoma (EMZL) of mucosa-associated lymphoid tissue (MALT) that affects the ocular adnexa, also known as ocular adnexal MALT lymphomas (OAML), are low-grade lymphomas that mostly affect elderly individuals. This study was conducted to explore the genetic and microbial drivers of OMAL, and unique morphometric phenotypes associated with these mutations and infections.
    Materials and methods: In this study, we performed targeted deep sequencing of 8 OAML cases to identify its potential genetic and microbial drivers. We additionally performed computational digital image analysis of cases to determine if morphologic features corresponded to genetic mutations and disease biology.
    Results: We identified TBL1XR1 as recurrently mutated in OAML (4/8), and mutations in several other oncogenes, tumor suppressors, transcription regulators, and chromatin remodeling genes. Morphologically, OAML cases with mutations in TBL1XR1 showed lymphoma cells with significantly lower circularity and solidity by computational digital image analysis (
    Conclusions: Our study showed recurrent mutations in TBL1XR1 are associated with unique morphometric phenotypes in OMAL cases. Additionally, mutations in genes associated with the methylation status of histone 3, nuclear factor (NF)-κB pathway, and NOTCH pathway were enriched in OMAL cases. Our findings have biologic and clinical implications as mutations in TBL1XR1 and other genes have the potential to be used as markers for the diagnosis of OAML, and also demonstrate a specific biologic phenotypic manifestation of TBL1XR1 mutations.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Conjunctival Neoplasms/genetics ; Conjunctival Neoplasms/pathology ; DNA Mutational Analysis ; Female ; Frameshift Mutation ; Humans ; Lymphoma, B-Cell, Marginal Zone/genetics ; Lymphoma, B-Cell, Marginal Zone/pathology ; Male ; Middle Aged ; Phenotype ; Receptors, Cytoplasmic and Nuclear/genetics ; Repressor Proteins/genetics
    Chemical Substances Receptors, Cytoplasmic and Nuclear ; Repressor Proteins ; TBL1XR1 protein, human
    Language English
    Publishing date 2020-06-19
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 82079-9
    ISSN 1460-2202 ; 0271-3683
    ISSN (online) 1460-2202
    ISSN 0271-3683
    DOI 10.1080/02713683.2020.1762228
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  7. Article ; Online: Adeno-Associated Virus-Mediated Dorsal Root Ganglion Toxicity in the New Zealand White Rabbit.

    Tien, Eric / Grubor, Branka / Kirkland, Melissa / Chan, Su Jing / van der Munnik, Nick / Xu, Wenlong / Henry, Kate / Hamann, Stefan / Wei, Cong / Lee, Wan-Hung / Gianni, Davide / Brennecke, Ashton / Nambiar, Kalyani / Chen, Jeron / Liu, Bin / Shen, Shen / Tremblay, Claudine / Plowey, Edward D / Trapa, Patrick /
    Fikes, James / Suh, Junghae / Morris, Dale

    Toxicologic pathology

    2024  , Page(s) 1926233241229808

    Abstract: Recombinant adeno-associated virus (AAV)-mediated degeneration of sensory neurons in the dorsal root ganglia (DRG) and trigeminal ganglia (TG) has been observed in non-human primates (NHPs) following intravenous (IV) and intrathecal (IT) delivery. ... ...

    Abstract Recombinant adeno-associated virus (AAV)-mediated degeneration of sensory neurons in the dorsal root ganglia (DRG) and trigeminal ganglia (TG) has been observed in non-human primates (NHPs) following intravenous (IV) and intrathecal (IT) delivery. Administration of recombinant AAV encoding a human protein transgene via a single intra-cisterna magna (ICM) injection in New Zealand white rabbits resulted in histopathology changes very similar to NHPs: mononuclear cell infiltration, degeneration/necrosis of sensory neurons, and nerve fiber degeneration of sensory tracts in the spinal cord and of multiple nerves. AAV-associated clinical signs and incidence/severity of histologic findings indicated that rabbits were equally or more sensitive than NHPs to sensory neuron damage. Another study using human and rabbit transgene constructs of the same protein demonstrated comparable changes suggesting that the effects are not an immune response to the non-self protein transgene. Rabbit has not been characterized as a species for general toxicity testing of AAV gene therapies, but these studies suggest that it may be an alternative model to investigate mechanisms of AAV-mediated neurotoxicity and test novel AAV designs mitigating these adverse effects.
    Language English
    Publishing date 2024-02-22
    Publishing country United States
    Document type Journal Article
    ZDB-ID 841009-4
    ISSN 1533-1601 ; 0192-6233
    ISSN (online) 1533-1601
    ISSN 0192-6233
    DOI 10.1177/01926233241229808
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  8. Article ; Online: TDP-43-stratified single-cell proteomics of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosis

    Amanda J. Guise / Santosh A. Misal / Richard Carson / Jen-Hwa Chu / Hannah Boekweg / Daisha Van Der Watt / Nora C. Welsh / Thy Truong / Yiran Liang / Shanqin Xu / Gina Benedetto / Jake Gagnon / Samuel H. Payne / Edward D. Plowey / Ryan T. Kelly

    Cell Reports, Vol 43, Iss 1, Pp 113636- (2024)

    2024  

    Abstract: Summary: A limitation of conventional bulk-tissue proteome studies in amyotrophic lateral sclerosis (ALS) is the confounding of motor neuron (MN) signals by admixed non-MN proteins. Here, we leverage laser capture microdissection and nanoPOTS single-cell ...

    Abstract Summary: A limitation of conventional bulk-tissue proteome studies in amyotrophic lateral sclerosis (ALS) is the confounding of motor neuron (MN) signals by admixed non-MN proteins. Here, we leverage laser capture microdissection and nanoPOTS single-cell mass spectrometry-based proteomics to query changes in protein expression in single MNs from postmortem ALS and control tissues. In a follow-up analysis, we examine the impact of stratification of MNs based on cytoplasmic transactive response DNA-binding protein 43 (TDP-43)+ inclusion pathology on the profiles of 2,238 proteins. We report extensive overlap in differentially abundant proteins identified in ALS MNs with or without overt TDP-43 pathology, suggesting early and sustained dysregulation of cellular respiration, mRNA splicing, translation, and vesicular transport in ALS. Together, these data provide insights into proteome-level changes associated with TDP-43 proteinopathy and begin to demonstrate the utility of pathology-stratified trace sample proteomics for understanding single-cell protein dynamics in human neurologic diseases.
    Keywords CP: Neuroscience ; CP: Molecular biology ; Biology (General) ; QH301-705.5
    Subject code 612
    Language English
    Publishing date 2024-01-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    More links

    Kategorien

  9. Article ; Online: Diagnosis of Chagasic Encephalitis by Sequencing of 28S rRNA Gene.

    Multani, Ashrit / Meer, Aabed / Smith, Darvin S / Kheraj, Malika N / Plowey, Edward D / Blackburn, Brian G

    Emerging infectious diseases

    2019  Volume 25, Issue 7, Page(s) 1370–1372

    Abstract: We report a case of chagasic encephalitis diagnosed by 28S rRNA sequencing. The diagnosis of chagasic encephalitis is challenging, given the broad differential diagnosis for central nervous system lesions in immunocompromised patients and low sensitivity ...

    Abstract We report a case of chagasic encephalitis diagnosed by 28S rRNA sequencing. The diagnosis of chagasic encephalitis is challenging, given the broad differential diagnosis for central nervous system lesions in immunocompromised patients and low sensitivity of traditional diagnostics. Sequencing should be part of the diagnostic armamentarium for potential chagasic encephalitis.
    MeSH term(s) Adult ; Chagas Disease/diagnosis ; Chagas Disease/drug therapy ; Chagas Disease/parasitology ; Humans ; Image-Guided Biopsy ; Immunocompromised Host ; Infectious Encephalitis/diagnosis ; Infectious Encephalitis/drug therapy ; Infectious Encephalitis/parasitology ; Magnetic Resonance Imaging ; Male ; RNA, Ribosomal, 28S/genetics ; Sequence Analysis, DNA ; Symptom Assessment ; Tomography, X-Ray Computed ; Treatment Outcome ; Trypanocidal Agents/therapeutic use ; Trypanosoma cruzi/classification ; Trypanosoma cruzi/genetics
    Chemical Substances RNA, Ribosomal, 28S ; Trypanocidal Agents
    Language English
    Publishing date 2019-06-17
    Publishing country United States
    Document type Case Reports ; Journal Article
    ZDB-ID 1380686-5
    ISSN 1080-6059 ; 1080-6040
    ISSN (online) 1080-6059
    ISSN 1080-6040
    DOI 10.3201/eid2507.180285
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  10. Article ; Online: BECN1/Beclin 1 sorts cell-surface APP/amyloid β precursor protein for lysosomal degradation.

    Swaminathan, Gayathri / Zhu, Wan / Plowey, Edward D

    Autophagy

    2016  Volume 12, Issue 12, Page(s) 2404–2419

    Abstract: The regulation of plasma membrane (PM)-localized transmembrane protein/receptor trafficking has critical implications for cell signaling, metabolism and survival. In this study, we investigated the role of BECN1 (Beclin 1) in the degradative trafficking ... ...

    Abstract The regulation of plasma membrane (PM)-localized transmembrane protein/receptor trafficking has critical implications for cell signaling, metabolism and survival. In this study, we investigated the role of BECN1 (Beclin 1) in the degradative trafficking of PM-associated APP (amyloid β precursor protein), whose metabolism to amyloid-β, an essential event in Alzheimer disease, is dependent on divergent PM trafficking pathways. We report a novel interaction between PM-associated APP and BECN1 that recruits macroautophagy/endosomal regulatory proteins PIK3C3 and UVRAG. We found that BECN1 promotes surface APP internalization and sorting predominantly to endosomes and endolysosomes. BECN1 also promotes the targeting of a smaller fraction of internalized APP to LC3-positive phagophores, suggesting a role for BECN1-dependent PM macroautophagy in APP degradation. Furthermore, BECN1 facilitates lysosomal degradation of surface APP and reduces the secretion of APP metabolites (soluble ectodomains, sAPP). The association between APP and BECN1 is dependent on the evolutionarily conserved domain (ECD) of BECN1 (amino acids 267-337). Deletion of a BECN1 ECD subregion (amino acids 285-299) did not impair BECN1- PIK3C3 interaction, PtdIns3K function or macroautophagy, but was sufficient to impair the APP-BECN1 interaction and BECN1's effects on surface APP internalization and degradation, resulting in increased secretion of sAPPs. Interestingly, both the BECN1-APP association and BECN1-dependent APP endocytosis and degradative trafficking were negatively regulated by active AKT. Our results further implicate phosphorylation of the BECN1 Ser295 residue in the inhibition of APP degradation by AKT. Our studies reveal a novel function for BECN1 in the sorting of a plasma membrane protein for endolysosomal and macroautophagic degradation.
    MeSH term(s) Amyloid beta-Protein Precursor/chemistry ; Amyloid beta-Protein Precursor/metabolism ; Autophagosomes/metabolism ; Beclin-1/chemistry ; Beclin-1/metabolism ; Cell Membrane/metabolism ; Endocytosis ; HEK293 Cells ; Humans ; Lysosomes/metabolism ; Metabolome ; Models, Biological ; Mutant Proteins/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Protein Binding ; Protein Domains ; Protein Transport ; Proteolysis ; Proto-Oncogene Proteins c-akt/metabolism
    Chemical Substances Amyloid beta-Protein Precursor ; Beclin-1 ; Mutant Proteins ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
    Language English
    Publishing date 2016-10-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2454135-7
    ISSN 1554-8635 ; 1554-8627
    ISSN (online) 1554-8635
    ISSN 1554-8627
    DOI 10.1080/15548627.2016.1234561
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

To top