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Aggrephagy: Selective Disposal of Protein Aggregates by Macroautophagy
Trond Lamark,Terje Johansen
International Journal of Cell Biology , 2012, DOI: 10.1155/2012/736905
Abstract: Protein aggregation is a continuous process in our cells. Some proteins aggregate in a regulated manner required for different vital functional processes in the cells whereas other protein aggregates result from misfolding caused by various stressors. The decision to form an aggregate is largely made by chaperones and chaperone-assisted proteins. Proteins that are damaged beyond repair are degraded either by the proteasome or by the lysosome via autophagy. The aggregates can be degraded by the proteasome and by chaperone-mediated autophagy only after dissolution into soluble single peptide species. Hence, protein aggregates as such are degraded by macroautophagy. The selective degradation of protein aggregates by macroautophagy is called aggrephagy. Here we review the processes of aggregate formation, recognition, transport, and sequestration into autophagosomes by autophagy receptors and the role of aggrephagy in different protein aggregation diseases. 1. Introduction Misfolded proteins result from mutations, incomplete translation giving defective ribosomal products (DRiPs), misfolding after translation, aberrant protein modifications, oxidative damage, and from failed assembly of protein complexes. Misfolded proteins expose hydrophobic patches that are normally buried internally in the native folded state. These hydrophobic surfaces trigger aggregation and can sequester normal proteins compromising their functionality [1]. To defend cells against the hazards caused by accumulation of misfolded proteins, different protein quality control machineries are active at several levels. Molecular chaperones, like the heat shock proteins (Hsp), recognize, assist folding, prevent aggregation, and attempt to repair misfolded proteins. However, if the damage is beyond repair, chaperone complexes, often in conjunction with interacting ubiquitin E3 ligases, channel the misfolded protein or protein aggregates to degradation pathways. 1.1. The UPS The two major degradation systems in the cell are the ubiquitin-proteasome system (UPS) and the lysosome (Figure 1). The UPS comprises the proteasome and the enzymatic cascade catalysing the ubiquitination of substrates destined for degradation in the proteasome. The prime tag for proteasomal degradation is a chain of 4 or more ubiquitin moieties covalently linked to lysine residue(s) of the target. Ubiquitin has 7 internal lysines (K6, K11, K27, K29, K33, K48, and K63) that can be linked, forming polyubiquitin chains [2, 3]. K48-linked polyubiquitin chains represent the canonical proteasomal degradation tag, but also
DOR/Tp53inp2 and Tp53inp1 Constitute a Metazoan Gene Family Encoding Dual Regulators of Autophagy and Transcription
Ana Sancho, Jordi Duran, Antonio García-Espa？a, Caroline Mauvezin, Endalkachew A. Alemu, Trond Lamark, Maria J. Macias, Rob DeSalle, Miriam Royo, David Sala, Javier U. Chicote, Manuel Palacín, Terje Johansen, Antonio Zorzano
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034034
Abstract: Human DOR/TP53INP2 displays a unique bifunctional role as a modulator of autophagy and gene transcription. However, the domains or regions of DOR that participate in those functions have not been identified. Here we have performed structure/function analyses of DOR guided by identification of conserved regions in the DOR gene family by phylogenetic reconstructions. We show that DOR is present in metazoan species. Invertebrates harbor only one gene, DOR/Tp53inp2, and in the common ancestor of vertebrates Tp53inp1 may have arisen by gene duplication. In keeping with these data, we show that human TP53INP1 regulates autophagy and that different DOR/TP53INP2 and TP53INP1 proteins display transcriptional activity. The use of molecular evolutionary information has been instrumental to determine the regions that participate in DOR functions. DOR and TP53INP1 proteins share two highly conserved regions (region 1, aa residues 28–42; region 2, 66–112 in human DOR). Mutation of conserved hydrophobic residues in region 1 of DOR (that are part of a nuclear export signal, NES) reduces transcriptional activity, and blocks nuclear exit and autophagic activity under autophagy-activated conditions. We also identify a functional and conserved LC3-interacting motif (LIR) in region 1 of DOR and TP53INP1 proteins. Mutation of conserved acidic residues in region 2 of DOR reduces transcriptional activity, impairs nuclear exit in response to autophagy activation, and disrupts autophagy. Taken together, our data reveal DOR and TP53INP1 as dual regulators of transcription and autophagy, and identify two conserved regions in the DOR family that concentrate multiple functions crucial for autophagy and transcription.
Dynamic subcellular localization of the mono-ADP-ribosyltransferase ARTD10 and interaction with the ubiquitin receptor p62
Henning Kleine, Andreas Herrmann, Trond Lamark, Alexandra H Forst, Patricia Verheugd, Juliane Lüscher-Firzlaff, Barbara Lippok, Karla LH Feijs, Nicolas Herzog, Elisabeth Kremmer, Terje Johansen, Gerhard Müller-Newen, Bernhard Lüscher
Cell Communication and Signaling , 2012, DOI: 10.1186/1478-811x-10-28
Abstract: We have characterized the subcellular localization of ARTD10 using live-cell imaging techniques. ARTD10 shuttles between the cytoplasmic and nuclear compartments. When nuclear, ARTD10 can interact with MYC as measured by bimolecular fluorescence complementation. The shuttling is controlled by a Crm1-dependent nuclear export sequence and a central ARTD10 region that promotes nuclear localization. The latter lacks a classical nuclear localization sequence and does not promote full nuclear localization. Rather this non-conventional nuclear localization sequence results in an equal distribution of ARTD10 between the cytoplasmic and the nuclear compartments. ARTD10 forms discrete and dynamic bodies primarily in the cytoplasm but also in the nucleus. These contain poly-ubiquitin and co-localize in part with structures containing the poly-ubiquitin receptor p62/SQSTM1. The co-localization depends on the ubiquitin-associated domain of p62, which mediates interaction with poly-ubiquitin.Our findings demonstrate that ARTD10 is a highly dynamic protein. It shuttles between the nuclear and cytosolic compartments dependent on a classical nuclear export sequence and a domain that mediates nuclear uptake. Moreover ARTD10 forms discrete bodies that exchange subunits rapidly. These bodies associate at least in part with the poly-ubiquitin receptor p62. Because this protein is involved in the uptake of cargo into autophagosomes, our results suggest a link between the formation of ARTD10 bodies and autophagy.Post-translational modifications refer to changes in the chemical appearance of proteins and occur, as the name implies, after proteins have been synthesized. These modifications frequently affect the behavior of proteins, including alterations in their activity or their subcellular localization. One of these modifications is the addition of ADP-ribose to a substrate from the cofactor NAD+. The enzymes responsible for this reaction are ADP-ribosyltransferases (ARTDs or previously
Effects of AGE Inhibition with Aminoguanidine in a Diabetic db/db Mouse Wound Model  [PDF]
Margrete Berdal, Trond Jenssen
Journal of Diabetes Mellitus (JDM) , 2014, DOI: 10.4236/jdm.2014.42017
Abstract:

Advanced glycation end products (AGEs) react non-enzymatically with tissue proteins to form irreversible structures involved in atherosclerosis, nephropathy, retinopathy, neuropathy, and wound healing. Studies on AGE-inhibitors have demonstrated possible prevention of diabetes complications. The present open label study was conducted on aminoguanidine (AGu), an inhibitor of AGE-formation, to examine potential effects on wound healing in diabetes type 2-like db/db mice during 5 - 6 weeks. The animals were divided into 4 groups: AGu from the day of wounding (day 0) topically and/or systemically in drinking water (1 g/L; group 1, n = 13); AGu 1 g/L in drinking water from 7 weeks prior to day 0 (group 2, n = 21); AGu 5 g/L in drinking water from 9 - 11 weeks prior to day 0 (group 3, n = 6); placebo controls (group 4, n = 8). Results: Glycated hemoglobin (A1C) was significantly lower in group 3 compared to the other groups (P < 0.05). Percentage change in A1C and body weight from baseline to the end of the experiment were both related to the AGu doses (1 or 5 g/L; A1C-change, P

Assessing the Outcome of Teacher Education Programs in Norway: An Analysis and Discussion of the Factor Structure in Domains of Teacher Practicum for Student Teachers at Three Norwegian Universities  [PDF]
Trond Solhaug, Thomas Dahl
Creative Education (CE) , 2016, DOI: 10.4236/ce.2016.710157
Abstract: This article contributes to our understanding of teacher education by presenting the results of a large pilot study of quality assessments of teacher education programs at three Norwegian universities. We present an assessment instrument that corresponds to the California Standards for Teaching Professions and the practice domains developed by Darling-Hammond. The research question is: To what extent does the reported five-factor structure in the reported revised instrument (Darling-Hammond) fit the Norwegian context? We have revised this instrument to better cover both the documented dimensions of teacher professionalism and the demands regarding teacher quality in Norwegian educational policy. This has been accomplished by incorporating and modifying the items of the Darling-Hammond instrument. The modification process involved a selection of students, teachers, teacher educators and a school headmaster who discussed the relevance and content validity of the items. The final questionnaire was piloted at three Norwegian universities in three different education programs, with the participation of 419 students. The results show high inter-correlation between the original practice domains of Darling-Hammond, but the original factor structure is reproduced and to some extent supported. The results are discussed, and we conclude that the reported assessment instrument is valid as a measure of the teacher education program contributions to students’ competence in the five reported domains of the teacher practicum. Therefore, the instrument may be used as an overall evaluation of the complete program or may be slightly modified using the item format to assess distinct aspects of teacher education.
The Exchange Rate Response of Credit-Constrained Exporters: The Role of Location  [PDF]
Trond-Arne Borgersen
Theoretical Economics Letters (TEL) , 2016, DOI: 10.4236/tel.2016.65096
Abstract: This paper analyses the exchange rate response of credit-constrained exporters and highlights location-driven balance sheet effects residing both on the real side and on the financial side of the economy. A model focusing the location of production relative to both credit markets and to the first and the second hand market for capital inputs introduces a number of balance-sheet driven exchange rate effects. When it comes to location, we consider four regimes, referred to as a developed, a developing and two transition economies that differ with respect to production technology and credit market structure, respectively. The export supply response differs both across countries at different stages of development as well as between countries with different strategies to globalisation.
The politics of local hospital reform: a case study of hospital reorganization following the 2002 Norwegian hospital reform
Trond Tjerbo
BMC Health Services Research , 2009, DOI: 10.1186/1472-6963-9-212
Abstract: The empirical part is a case study of the restructuring process in Innlandet Hospital Trust (IHT), which was one of the largest enterprise established after the hospital reform and where the vision for restructuring was clearly set. Different sources of qualitative data are used in the analysis. These include interviews with key actors, observational data and document studies.The analysis demonstrates how the new professional leaders at first acted in accordance with the intentions of the hospital reform, but soon chose to avoid the more ambitious plans for restructuring the hospital structure and in fact reintroduced local politics into the decision-making process. The analysis further illustrates how local networks and engagement of political representatives from all levels of government complicated the decision-making process surrounding local structural reforms. Local political representatives teamed up with other actors and created powerful networks. At the same time, national politicians had incentives to involve themselves in the processes as supporters of the status quo.Because of the incentives that faced political actors and the controversial nature of major hospital reforms, the removal of local politicians and the centralization of ownership did not necessarily facilitate reforms in the hospital structure. Keeping politics at an arm's length may simply be unrealistic and further complicate the politics of local hospital reforms.Because of a decentralized settlement pattern and great geographical distances, local hospitals have played an important role in the provision of specialist health care in Norway. However, the decentralized hospital structure may have negative effects on clinical quality [1,2], and it is generally regarded as costly. The need for structural changes within the hospital sector was emphasized in several reviews and royal commissions leading up to the 2002 hospital reform, when the central state took over ownership of the hospitals [3
New Labour's state of health: political economy, public policy and the NHS
Trond Tjerbo
International Journal of Integrated Care , 2007,
Abstract:
A Recursive Algorithm for the Reduction of Block Diagrams
Trond Andresen
Modeling, Identification and Control , 1991, DOI: 10.4173/mic.1991.1.4
Abstract: A recursive algorithm to compute input-output relationships in a network of rational transfer functions (a block diagram) is derived. Initially all transfer functions are disconnected. For each step in the algorithm, a new transfer function in the network is connected to the system. One application of the algorithm is to find the transfer matrix of a linear multivariable system given on state space form. The algorithm is advantageous when one needs repeated computations of a transfer matrix in a multivariable system for successive changes in one or a few parameters in the system. The transfer matrix for a multivariable linear system with one time delay, and the exact frequency response in the case of several time delays, are derived.
A Logarithmic-Amplitude Polar Diagram
Trond Andresen
Modeling, Identification and Control , 2001, DOI: 10.4173/mic.2001.2.1
Abstract: A polar diagram where the amplitude of the transfer function is on a logarithmic scale, is presented. This gives a one-size-fits-all diagram with no need for zooming in and out, and no need for additional reasoning about infinite-radius encirclements when there are poles on the imaginary axis - as opposed to what is usually neccessary with the standard polar (Nyquist-) diagram. All properties needed for stability considerations are upheld, such as encirclements, gain and phase margins. The path for s in the loop transfer function is carefully chosen with regard to possible poles on the imaginary axis. Small excursions into the right half plane in the form of arcs of different-sized logarithmic spirals result in corresponding large but finite arcs that do not overlap in the logarithmic polar plots.
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