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Author : Walter J. Fader
Publisher : Unknown
Page : 44 pages
File Size : 47,8 Mb
Release : 1964
Category : Perturbation (Mathematics)
ISBN : UOM:39015095035872
Author : Vijay Kumar,Manoj Kumar Jaiswal
Publisher : Academic Press
Page : 272 pages
File Size : 42,7 Mb
Release : 2021-10-23
Category : Medical
ISBN : 9780128204405
Aggregates of the TAR DNA binding protein 43 (TDP-43), are hallmark features of the neurodegenerative diseases Amyotrophic Lateral Sclerosis (ALS) and frontotemporal dementia (FTD), with overlapping clinical, genetic and pathological features. TDP-43 and Neurodegeneration: From Bench to Bedside summarizes new findings in TDP-43 pathobiology and proteinopathies. The book summarizes TDP-43’s structure, function, biology, misfolding, aggregation, pathogenesis and therapeutics. It includes autophagy-mediated therapy, role of stress granule, novel genetic, cell culture-based models, systems biology for precision medicine, development of stem cells and mechanism-based therapies that can target ALS and other related neurodegenerative diseases. This book is written for neuroscientists, neurologists, clinicians, advanced graduate students, drug discovery researchers, as well as cellular and molecular biologists involved in ALS, motor neuron disease (MND) and other neurodegenerative disorders. Reviews TDP-43 structure, folding, function, and pathology Identifies TDP-43 role in ALS, FTP, and other neurodegenerative diseases Presents a systems and precision biology perspective of TDP-43 Discusses therapeutics of TDP-43 proteinopathies Translates bench research to application bedside
Author : Christopher Sackmann
Publisher : Linköping University Electronic Press
Page : 73 pages
File Size : 51,7 Mb
Release : 2019-10-14
Category : Electronic
ISBN : 9789175190150
Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS) are disorders characterized by the progressive deposition of proteinaceous inclusions throughout the brain in a predictable manner. Each disease is described by the involvement of different misfolded and aggregated proteins (AD, amyloid-? and tau; PD, ?-synuclein; ALS and FTLD, TDP-43) that spread between anatomically connected brain regions, causing cell death in previously healthy regions. Disease progresses as these aggregated proteins spread throughout the brain in a prion-like fashion. Oligomeric forms of these proteins (aggregates comprising of ?3-30 individual proteins) are thought to be the most relevant to disease, as they are capable of prion-like propagation and can cause cellular toxicity. The work in this thesis aims to elucidate the mechanisms by which different neurodegenerative disease related proteins (amyloid-?, ?-synuclein and TDP-43) are taken up and transferred between cells, and the effects exerted by these proteins on downstream cells. Paper I examined the uptake and cell to cell transmission of oligomeric ?-synuclein (?-syn). Using a 3D co-culture model, we determined that ?-syn (monomeric, oligomeric and fibrillar assemblies) were readily taken up and transferred between neuron-like cells, and that this transfer was mediated by an endosomal/lysosomal mechanism. It was also determined that larger ?-syn assemblies (oligomers and fibrils) were found in donor and acceptor cells more frequently than monomeric ?-syn, which we speculate is a due to the larger aggregates’ resistance to cellular proteases. In Paper II, we identified a novel mechanism for the uptake of oligomeric proteins, in the discovery that the gap junction channel protein connexin 32 mediates the uptake of ?-syn oligomers in a preferential manner. Gap junction proteins act as a means of communication between adjacent cells, forming a transmembrane pore to facilitate the passage of small molecules. Here, we determined that connexin 32 drives the preferential uptake of oligomeric ?-syn relative to monomeric and fibrillar ?-syn. This system was not exclusive to ?-syn however, as the preferential uptake of oligomeric amyloid-? (A?) was also observed. In addition to the uptake of oligomers, we observed that increased ?-syn expression elicited the increased expression of connexin 32, in a positive feedback mechanism. When connexin 32 was inhibited pharmacologically or knocked out using CRISPR/Cas9, the preferential uptake of oligomers was abolished. These phenomena were also observed in oligodendrocytes (the accumulation of oligomeric ?-syn in oligodendrocytes is a hallmark of Multiple Systems Atrophy), three different mouse models of ?-syn overexpression, as well as in post-mortem human tissues. Paper III undertook the investigation of cell to cell transfer of TDP-43. Although it was recently confirmed that TDP-43 propagates throughout the brain in a prion-like fashion, it remains unclear how post-translational modifications of TDP-43 affect its propensity to be transferred between cells. This leaves a gap in the understanding of how TDP-43 proteinopathies progress, as post-translationally modified TDP-43 is understood to be critical to pathogenesis. To study this, we generated several TDP-43 cell lines, expressing full-length TDP-43 or C-/N-terminally truncated fragments, known contributors to TDP-43 proteinopathies. Using the 3D co-culture model, we determined that preservation of the N-terminus of TDP-43 enhanced its ability to transmit between cells, whereas an intact the C-terminus reduced transfer. Additionally, since we have previously shown that both oligomeric A? and ?-syn are incorporated into extracellular vesicles (EVs) such as exosomes, and that these EVs can sufficiently mediate the transfer of protein oligomers to downstream cells, we investigated whether this was also true for TDP-43. We demonstrated that full-length TDP-43 and TDP-43 fragments could be found within EVs generated by these cells, but that these EVs were unable to propagate the protein to downstream cells. Instead, the transmission of TDP-43 occurs in a manner dependent upon physical proximity between cells, possibly across the synaptic cleft itself. Next, we studied the acute effects exerted by oligomeric A? upon healthy neurons in order to understand the earliest effects of oligomeric A? challenge. In Paper IV, we used iPSC-derived neurons generated from human donors expressing different amyloid-? precursor protein (APP) genes, one harbouring the familial AD-causing V717I London mutation, the other expressing WT APP. After differentiating these cells into functional neurons in vitro, the neurons were challenged with acute exposure to exogenous oligomeric A? and analyzed by LC-MS/MS to observe the early effects. By analyzing the proteome and phosphoproteome of these cells, we identified many proteins and phosphoproteins that were up- or down-regulated in response to oligomeric A? at this early timepoint. Among these changes, oligomeric A? caused the downregulation of TDP-43, heterogeneous nuclear ribonucleoproteins, and coatomer complex I proteins. Conversely, increases were observed in 20S proteasome subunits and vesicle associated proteins VAMP1/2. We also observed the differential phosphorylation of tau at serine 208, indicating that phosphorylation at this residue might be an important early event in tauopathy. Altogether, the work described in this thesis has provided new understanding as to how different neurodegenerative disease related proteins are taken up and transferred between cells. In doing so, we have identified some of the mechanisms by which this spreading occurs, and that the changes elicited by these toxic oligomeric proteins are rapid and widespread. By learning about these processes, we have identified novel targets that could be used in the development of disease modifying therapeutics.
Author : Anonim
Publisher : ScholarlyEditions
Page : 168 pages
File Size : 40,6 Mb
Release : 2012-12-26
Category : Medical
ISBN : 9781464999352
TDP-43 Proteinopathies—Advances in Research and Treatment: 2012 Edition is a ScholarlyEditions™ eBook that delivers timely, authoritative, and comprehensive information about TDP-43 Proteinopathies. The editors have built TDP-43 Proteinopathies—Advances in Research and Treatment: 2012 Edition on the vast information databases of ScholarlyNews.™ You can expect the information about TDP-43 Proteinopathies in this eBook to be deeper than what you can access anywhere else, as well as consistently reliable, authoritative, informed, and relevant. The content of TDP-43 Proteinopathies—Advances in Research and Treatment: 2012 Edition has been produced by the world’s leading scientists, engineers, analysts, research institutions, and companies. All of the content is from peer-reviewed sources, and all of it is written, assembled, and edited by the editors at ScholarlyEditions™ and available exclusively from us. You now have a source you can cite with authority, confidence, and credibility. More information is available at http://www.ScholarlyEditions.com/.
Author : Anonim
Publisher : ScholarlyEditions
Page : 59 pages
File Size : 53,7 Mb
Release : 2012-01-09
Category : Medical
ISBN : 9781464936418
TDP-43 Proteinopathies: Advances in Research and Treatment: 2011 Edition is a ScholarlyBrief™ that delivers timely, authoritative, comprehensive, and specialized information about TDP-43 Proteinopathies in a concise format. The editors have built TDP-43 Proteinopathies: Advances in Research and Treatment: 2011 Edition on the vast information databases of ScholarlyNews.™ You can expect the information about TDP-43 Proteinopathies in this eBook to be deeper than what you can access anywhere else, as well as consistently reliable, authoritative, informed, and relevant. The content of TDP-43 Proteinopathies: Advances in Research and Treatment: 2011 Edition has been produced by the world’s leading scientists, engineers, analysts, research institutions, and companies. All of the content is from peer-reviewed sources, and all of it is written, assembled, and edited by the editors at ScholarlyEditions™ and available exclusively from us. You now have a source you can cite with authority, confidence, and credibility. More information is available at http://www.ScholarlyEditions.com/.
Author : Anonim
Publisher : DIANE Publishing
Page : 396 pages
File Size : 48,9 Mb
Release : 2024-07-01
Category : Electronic
ISBN : 9781437900040
Author : Dr. R. K. Thukral
Publisher : Datanet India Pvt. Ltd.
Page : 150 pages
File Size : 41,5 Mb
Release : 2018-01-01
Category : Electronic
ISBN : 9789387415010
ANDHRA PRADESH ASSEMBLY FACTBOOK : ACHANTA ASSEMBLY - This book is a special publication of Datanet India and provides Key Electoral Data of ACHANTA Assembly Constituency (1952- 2017). For more about ANDHRA PRADESH Assembly Factbook : ACHANTA Assembly check the Contents section in Sample view.
Author : Varda Shoshan-Barmatz,Carlos Pérez-Plasencia,Sandra Casimiro,Marta Martins,João Pessoa
Publisher : Frontiers Media SA
Page : 535 pages
File Size : 51,6 Mb
Release : 2022-08-03
Category : Medical
ISBN : 9782889765812
Author : United Nations Relief and Rehabilitation Administration. Council. Standing Technical Committee on Displaced Persons
Publisher : Unknown
Page : 600 pages
File Size : 47,7 Mb
Release : 1944
Category : Electronic
ISBN : UCAL:C2541345
Author : United Nations Relief and Rehabilitation Administration. Council. Standing Technical Committee on Displaced Persons. Subcommittee on Displaced Persons for the Western Hemisphere
Publisher : Unknown
Page : 22 pages
File Size : 51,8 Mb
Release : 1945
Category : Electronic
ISBN : UCAL:C2541334
Author : Anonim
Publisher : Unknown
Page : 448 pages
File Size : 50,5 Mb
Release : 1985
Category : Local transit
ISBN : NWU:35556021346242
Author : Ambrose Pinto
Publisher : Unknown
Page : 214 pages
File Size : 45,5 Mb
Release : 2000
Category : Elections
ISBN : UOM:39015052256172
With reference to India.
Author : Paul Wallace,Ramashray Roy
Publisher : SAGE Publications Pvt. Limited
Page : 464 pages
File Size : 51,8 Mb
Release : 2003-05-27
Category : Political Science
ISBN : 0761995986
This book examines the consequences and results of the 1999 general elections in light of the recent developments in Indian politics and the Indian party system.
Author : Anonim
Publisher : Unknown
Page : 370 pages
File Size : 47,7 Mb
Release : 1976
Category : Great Britain
ISBN : UOM:39015034755473
Author : Arne Jon Arneson,Stacie Williams
Publisher : Madison, Wis. : Index House
Page : 172 pages
File Size : 46,9 Mb
Release : 1986
Category : Harpsichord music
ISBN : UCAL:B4338091