Ändra sökning
Avgränsa sökresultatet
1 - 21 av 21
RefereraExporteraLänk till träfflistan
Permanent länk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Träffar per sida
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sortering
  • Standard (Relevans)
  • Författare A-Ö
  • Författare Ö-A
  • Titel A-Ö
  • Titel Ö-A
  • Publikationstyp A-Ö
  • Publikationstyp Ö-A
  • Äldst först
  • Nyast först
  • Skapad (Äldst först)
  • Skapad (Nyast först)
  • Senast uppdaterad (Äldst först)
  • Senast uppdaterad (Nyast först)
  • Disputationsdatum (tidigaste först)
  • Disputationsdatum (senaste först)
  • Standard (Relevans)
  • Författare A-Ö
  • Författare Ö-A
  • Titel A-Ö
  • Titel Ö-A
  • Publikationstyp A-Ö
  • Publikationstyp Ö-A
  • Äldst först
  • Nyast först
  • Skapad (Äldst först)
  • Skapad (Nyast först)
  • Senast uppdaterad (Äldst först)
  • Senast uppdaterad (Nyast först)
  • Disputationsdatum (tidigaste först)
  • Disputationsdatum (senaste först)
Markera
Maxantalet träffar du kan exportera från sökgränssnittet är 250. Vid större uttag använd dig av utsökningar.
  • 1.
    Ajayi, Abiodun
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Karlström, Victor
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Ström, Anna-Lena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    NOX1 and p53 cross-talk in SCA7 polyglutamine toxicityManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Spinocerebellar ataxia type 7 (SCA7) is one of nine neurodegenerative disorders caused by expanded polyglutamine repeats. Common toxic gain-of-function mechanisms, including oxidative stress and metabolic dysfunction, have been proposed in these disorders. In a recent study we identified increased activity of the ROS producing NADPH oxidase 1 (NOX1) enzyme and reduced activity of the p53 transcription factor as contributing factors to the oxidative stress and metabolic dysfunction in a SCA7 model. In this study we further investigate the molecular mechanisms behind the altered NOX1 and p53 activity, as well as how these two molecules cross-talk to promote oxidative stress, metabolic dysfunction and toxicity in SCA7. We show that increased NOX1 protein stability, as well as alteration of p53-mediated regulation of NOX1 mRNA levels, contributes to the elevated NOX1 expression in SCA7 cells. Furthermore, we show that the enhance NOX1 activity in SCA7 cells is associated with increased oxidation of p53 and promotes a shift in the p53 sub-cellular localization, as well reduction of soluble p53 levels. Taken together, our results suggest that in SCA7 cells a feed-forward loop between NOX1 and p53 is induced. In this loop NOX1-mediated p53 oxidation results in altered p53 localization and reduced p53 transcriptional activity. In turn, the reduced p53 transcriptional activity promotes the activation of NOX1 mRNA and activity. This loop then contributes to the metabolic dysregulation, oxidative stress and toxicity in SCA7 cells.

  • 2.
    Ajayi, Abiodun
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Yu, Xin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Lindberg, Staffan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Langel, Ülo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Ström, Anna-Lena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Expanded ataxin-7 cause toxicity by inducing ROS production from NADPH oxidase complexes in a stable inducible Spinocerebellar ataxia type 7 (SCA7) model2012Ingår i: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 13, artikel-id 86Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Spinocerebellar ataxia type 7 (SCA7) is one of nine inherited neurodegenerative disorders caused by polyglutamine (polyQ) expansions. Common mechanisms of disease pathogenesis suggested for polyQ disorders include aggregation of the polyQ protein and induction of oxidative stress. However, the exact mechanism(s) of toxicity is still unclear. Results: In this study we show that expression of polyQ expanded ATXN7 in a novel stable inducible cell model first results in a concomitant increase in ROS levels and aggregation of the disease protein and later cellular toxicity. The increase in ROS could be completely prevented by inhibition of NADPH oxidase (NOX) complexes suggesting that ATXN7 directly or indirectly causes oxidative stress by increasing superoxide anion production from these complexes. Moreover, we could observe that induction of mutant ATXN7 leads to a decrease in the levels of catalase, a key enzyme in detoxifying hydrogen peroxide produced from dismutation of superoxide anions. This could also contribute to the generation of oxidative stress. Most importantly, we found that treatment with a general anti-oxidant or inhibitors of NOX complexes reduced both the aggregation and toxicity of mutant ATXN7. In contrast, ATXN7 aggregation was aggravated by treatments promoting oxidative stress. Conclusion: Our results demonstrates that oxidative stress contributes to ATXN7 aggregation as well as toxicity and show that anti-oxidants or NOX inhibition can ameliorate mutant ATXN7 toxicity.

  • 3.
    Ajayi, Abiodun
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Yu, Xin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Ström, Anna-Lena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    The role of NADPH oxidase (NOX) enzymes in neurodegenerative disease2013Ingår i: Frontiers in Biology, ISSN 1674-7992, Vol. 8, nr 2, s. 175-188Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recently, mounting evidence implicating reactive oxygen species (ROS) generated by NADPH oxidase(NOX) enzymes in the pathogenesis of several neurodegenerative diseases including Amyotrophic lateral sclerosis(ALS), Alzheimer’s (AD), Parkinson’s (PD) and polyglutamine disease, have arisen. NOX enzymes are transmembraneproteins and generate reactive oxygen species by transporting electrons across lipid membranes. Under normal healthyconditions, low levels of ROS produced by NOX enzymes have been shown to play a role in neuronal differentiation andsynaptic plasticity. However, in chronic neurodegenerative diseases over-activation of NOX in neurons, as well as inastrocytes and microglia, has been linked to pathogenic processes such as oxidative stress, exitotoxicity andneuroinflammation. In this review, we summarize the current knowledge about NOX functions in the healthy centralnervous system and especially the role of NOX enzymes in neurodegenerative disease processes.

  • 4.
    Ajayi, Abiodun
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Yu, Xin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Wahlo-Svedin, Carolina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Ström, Anna-Lena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Polyglutamine expanded ataxin-7 alters NOX1 activity and cellular metabolism2013Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Spinocerebellar ataxia type 7 (SCA7) is one of nine inherited neurodegenerative disorders caused by polyglutamine (polyQ) expansions. Common pathogenic mechanisms, including oxidative stress and metabolic dysfunction, have been implicated in polyQ disease. However, the exact toxic mechanism(s) is still unclear. We have previously demonstrated that expression of the SCA7 disease protein, ATXN7, results in oxidative stress and toxicity via activation of ROS-producing NADPH oxidase (NOX) enzymes. In this study, we show that mutant ATXN7 specifically up-regulates and activates the NOX1 family member. Furthermore, we show that the increased NOX1 activity is linked with a metabolic shift, similar to the Warburg effect, and reduced energy levels. Reduction of the NOX1-mediated ROS production reverse the metabolic shift and rescue the ATXN7 induced toxicity. These data suggest that NOX1-mediated metabolic alterations and energy deficit could play a role in SCA7 pathology and possibly in other polyQ diseases.

  • 5.
    Ajayi, Abiodun
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Yu, Xin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Wahlo-Svedin, Carolina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Tsirigotaki, Galateia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Karlström, Victor
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Ström, Anna-Lena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Altered p53 and NOX1 activity cause bioenergetic defects in a SCA7 polyglutamine disease model2015Ingår i: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1847, nr 4-5, s. 418-428Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Spinocerebellar ataxia type 7 (SCA7) is one of the nine neurodegenerative disorders caused by expanded polyglutamine (polyQ) domains. Common pathogenic mechanisms, including bioenergetics defects, have been suggested for these so called polyQ diseases. However, the exact molecular mechanism(s) behind the metabolic dysfunction is still unclear. In this study we identified a previously unreported mechanism, involving disruption of p53 and NADPH oxidase 1 (NOX1) activity, by which the expanded SCA7 disease protein ATXN7 causes metabolic dysregulation. The NOX1 protein is known to promote glycolytic activity, whereas the transcription factor p53 inhibits this process and instead promotes mitochondrial respiration. In a stable inducible PC12 model of SCA7, p53 and mutant ATXN7 co-aggregated and the transcriptional activity of p53 was reduced, resulting in a 50% decrease of key p53 target proteins, like AIF and TIGAR. In contrast, the expression of NOX1 was increased approximately 2 times in SCA7 cells. Together these alterations resulted in a decreased respiratory capacity, an increased reliance on glycolysis for energy production and a subsequent 20% reduction of ATP in SCA7 cells. Restoring p53 function, or suppressing NOX1 activity, both reversed the metabolic dysfunction and ameliorated mutant ATXN7 toxicity. These results hence not only enhance the understanding of the mechanisms causing metabolic dysfunction in SCA7 disease, but also identify NOX1 as a novel potential therapeutic target in SCA7 and possibly other polyQ diseases.

  • 6.
    Bergqvist, Cecilia
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Niss, Frida
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Figueroa, Ricardo A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Beckman, Marie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Karolinska Institutet, Sweden.
    Maksel, Danuta
    Jafferali, Mohammed H.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Kulyté, Agné
    Ström, Anna-Lena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Hallberg, Einar
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Monitoring of chromatin organization in live cells by FRIC. Effects of the inner nuclear membrane protein Samp12019Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 47, nr 9, artikel-id e49Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In most cells, transcriptionally inactive heterochromatin is preferentially localized in the nuclear periphery and transcriptionally active euchromatin is localized in the nuclear interior. Different cell types display characteristic chromatin distribution patterns, which change dramatically during cell differentiation, proliferation, senescence and different pathological conditions. Chromatin organization has been extensively studied on a cell population level, but there is a need to understand dynamic reorganization of chromatin at the single cell level, especially in live cells. We have developed a novel image analysis tool that we term Fluorescence Ratiometric Imaging of Chromatin (FRIC) to quantitatively monitor dynamic spatiotemporal distribution of euchromatin and total chromatin in live cells. A vector (pTandemH) assures stoichiometrically constant expression of the histone variants Histone 3.3 and Histone 2B, fused to EGFP and mCherry, respectively. Quantitative ratiometric (H3.3/H2B) imaging displayed a concentrated distribution of heterochromatin in the periphery of U2OS cell nuclei. As proof of concept, peripheral heterochromatin responded to experimental manipulation of histone acetylation. We also found that peripheral heterochromatin depended on the levels of the inner nuclear membrane protein Samp1, suggesting an important role in promoting peripheral heterochromatin. Taken together, FRIC is a powerful and robust new tool to study dynamic chromatin redistribution in live cells.

  • 7.
    Koistinen, Niina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Menon, Preeti
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Ivanova, Elena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Kumcu, Michael
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Iverfeldt, Kerstin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Ström, Anna-Lena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    ADAM10 dependent nuclear localization of the amyloid-β precursor protein-binding protein Fe65 is attenuated in neuronally differentiated SH-SY5Y cellsManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Fe65 is a brain enriched adaptor protein involved in various cellular processes. These processes may include regulated intramembrane proteolysis (RIP) of the amyloid-β precursor protein (APP) and transcriptional activation. However, much still needs to be learned regarding the regulation of Fe65 functions throughout the cell. In this study we therefore investigated the role of Fe65 Ser228 phosphorylation and α-secretase processing of proteins like APP undergoing RIP, in the regulation of Fe65 nuclear localization. We found that although Ser228 phosphorylation is not a major regulator of Fe65 nuclear localization, mutation of Ser228 results in an increased interaction with APP, suggesting that the N-terminal domain of Fe65 may have a more prominent role in mediating the Fe65-APP interaction than previously thought.  Moreover, we found that α-secretase processing play a key role in promoting Fe65 nuclear localization, but while ADAM10 play a considerable role in undifferentiated cells, other α-secretases take a more prominent part in releasing Fe65 from the plasma membrane in differentiated cells.      

  • 8.
    Koistinen, Niina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Menon, Preeti
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Iverfeldt, Kerstin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Ström, Anna-Lena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    APP Ser675 phosphorylation affects α-secretase processing resulting in decreased secretion of the neuroprotective ectodomain sAPPαManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by abnormal deposition of the amyloid-β (Aβ) peptide. Aβ is produced after amyloidogenic (β-secretase) processing of the transmembrane amyloid precursor protein (APP). However, APP can also be processed by α-secretases, instead resulting in release of neuroprotective sAPPα.  Growing evidence indicate that aberrant post-translational modifications of APP may play a pivotal role in AD pathogenesis by dysregulating APP processing. APP Ser675 phosphorylation occurs in AD brains and here we for the first time show that this phosphorylation decreases the release of sAPPα, while the level of an alternative APP-C83-CTF fragment is increased. Moreover, we found that while APP Ser675 phosphorylation increased the APP-Fe65 interaction, the level of APP at the plasma membrane were unaltered. Taken together these results suggest that APP Ser675 phosphorylation alters the α-secretase processing of APP at the plasma membrane. As α-secretase processing of APP is an essential step in decreasing the generation of Aβ these results suggest that Ser675 phosphorylation could contribute to AD pathology.

  • 9. Liu, Rujuan
    et al.
    Ström, Anna-Lena
    University of Kentucky, USA.
    Zhai, Jianjun
    Gal, Jozsef
    Bao, Shilai
    Gong, Weimin
    Zhu, Haining
    Enzymatically inactive adenylate kinase 4 interacts with mitochondrial ADP/ATP translocase2009Ingår i: International Journal of Biochemistry and Cell Biology, ISSN 1357-2725, E-ISSN 1878-5875, Vol. 41, nr 6, s. 1371-1380Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Adenylate kinase 4 (AK4) is a unique member with no enzymatic activity in vitro in the adenylate kinase (AK) family although it shares high sequence homology with other AKs. It remains unclear what physiological function AK4 might play or why it is enzymatically inactive. In this study, we showed increased AK4 protein levels in cultured cells exposed to hypoxia and in an animal model of the neurodegenerative disease amyotrophic lateral sclerosis. We also showed that short hairpin RNA (shRNA)-mediated knockdown of AK4 in HEK293 cells with high levels of endogenous AK4 resulted in reduced cell proliferation and increased cell death. Furthermore, we found that AK4 over-expression in the neuronal cell line SH-SY5Y with low endogenous levels of AK4 protected cells from H(2)O(2) induced cell death. Proteomic studies revealed that the mitochondrial ADP/ATP translocases (ANTs) interacted with AK4 and higher amount of ANT was co-precipitated with AK4 when cells were exposed to H(2)O(2) treatment. In addition, structural analysis revealed that, while AK4 retains the capability of binding nucleotides, AK4 has a glutamine residue instead of a key arginine residue in the active site well conserved in other AKs. Mutation of the glutamine residue to arginine (Q159R) restored the adenylate kinase activity with GTP as substrate. Collectively, these results indicate that the enzymatically inactive AK4 is a stress responsive protein critical to cell survival and proliferation. It is likely that the interaction with the mitochondrial inner membrane protein ANT is important for AK4 to exert the protective benefits to cells under stress.

  • 10.
    Menon, Preeti
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Koistinen, Niina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Iverfeldt, Kerstin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ström, Anna-Lena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    APP Ser675 phosphorylation alters APP processing resulting in decreased secretion of neuroprotective ectodomain sAPPalphaManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by abnormal deposition of amyloid-β (Aβ) peptides. Aβ is a cleavage product of the amyloid precursor protein (APP) and aberrant post-translational modifications of APP could alter APP processing and increased Aβ generation. In AD brain, seven different residues, including Ser675 (APP695 numbering), in the APP cytoplasmic domain has been found to be phosphorylated. Here we for the first time show that phosphorylation of APP at Ser675 alters APP processing, without affecting the plasma membrane level of APP. The altered processing results in increased expression of an alternative CTF, similar in size to β-secretase generated C99, but sensitive to metalloprotease inhibitors. Moreover, reduced secretion of sAPPα, as well as total sAPP, was observed. Taken together these findings suggest that Ser675 phosphorylation likely promote APP processing by the metalloprotease Meprin β, an alternative β-secretase localized at the plasma membrane and known to generate a C99 like CTF, but no sAPP fragments. As previous studies have shown that the Meprin β CTF can be furthered processed by γ-secretase yielding highly aggregate prone, truncated Aβ peptides, an increased Meprin β processing of APP upon Ser675 phosphorylation could contribute to AD pathology. It will hence be of importance to clarify how APP Ser675 phosphorylation could promote Meprin β cleavage at the plasma membrane in future studies.

  • 11.
    Niss, Frida
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Zaidi, Wajiha
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Papadopoulou, Elisavet
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Hallberg, Einar
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ström, Anna-Lena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Polyglutamine expanded Ataxin-7 alters FUS localization and function in a SCA7 cell modelManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Polyglutamine (polyQ) diseases, such as Spinocerebellar ataxia type 7, are caused by the expansion of a CAG/polyglutamine repeat in a disease specific gene/protein. Misfolding and aggregation of the expanded protein can be observed in all polyQ disorders and sequestration of vital proteins into the aggregates formed have been suggested as a common pathological mechanism. FUS, an RNA binding protein, is frequently observed in polyglutamine aggregates. However, whether or not FUS disruption contributes to polyQ pathology is not clear.

    To address this question we used confocal microscopy, cell fractionation, filter traps and western blot, to study how FUS localization and function is affected by the SCA7 disease protein ataxin-7 (ATXN7). We found that aggregates formed by polyQ expanded ATXN7 were to a high degree also FUS positive and FUS re-distributed into the insoluble cell fraction together with mutant ATXN7. Moreover, a shift in abundance of FUS from the nucleus to the cytoplasm was observed and associated with altered levels of FUS regulated mRNAs in mutant ATXN7 expressing cells. However, some of the affected mRNAs are also regulated by the RNA binding protein TDP-43, which we could also show co-localized with ATXN7 aggregates using microscopy. Moreover, increased phosphorylation of serine 409/410 in TDP-43, which has been linked to TDP-43 neurotoxicity, could be observed in mutant ATXN7 expressing cells. Taken together, these findings lead us to conclude that disruption of FUS and also TDP-43 could potentially play a role in SCA7 pathology.

  • 12. Ramesh Babu, J.
    et al.
    Lamar Seibenhener, M.
    Peng, Junmin
    Ström, Anna-Lena
    University of Kentucky, USA.
    Kemppainen, Robert
    Cox, Nancy
    Zhu, Haining
    Wooten, Michael C.
    Diaz-Meco, María T.
    Moscat, Jorge
    Wooten, Marie W.
    Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration2008Ingår i: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 106, nr 1, s. 107-120Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The signaling adapter p62 plays a coordinating role in mediating phosphorylation and ubiquitin-dependent trafficking of interacting proteins. However, there is little known about the physiologic role of this protein in brain. Here, we report age-dependent constitutive activation of glycogen synthase kinase 3beta, protein kinase B, mitogen-activated protein kinase, and c-Jun-N-terminal kinase in adult p62(-/-) mice resulting in hyperphosphorylated tau, neurofibrillary tangles, and neurodegeneration. Biochemical fractionation of p62(-/-) brain led to recovery of aggregated K63-ubiquitinated tau. Loss of p62 was manifested by increased anxiety, depression, loss of working memory, and reduced serum brain-derived neurotrophic factor levels. Our findings reveal a novel role for p62 as a chaperone that regulates tau solubility thereby preventing tau aggregation. This study provides a clear demonstration of an Alzheimer-like phenotype in a mouse model in the absence of expression of human genes carrying mutations in amyloid-beta protein precursor, presenilin, or tau. Thus, these findings provide new insight into manifestation of sporadic Alzheimer disease and the impact of obesity.

  • 13. Shi, Ping
    et al.
    Ström, Anna-Lena
    University of Kentucky, USA.
    Gal, Jozsef
    Zhu, Haining
    Effects of ALS-related SOD1 mutants on dynein- and KIF5-mediated retrograde and anterograde axonal transport2010Ingår i: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1802, nr 9, s. 707-716Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Transport of material and signals between extensive neuronal processes and the cell body is essential to neuronal physiology and survival. Slowing of axonal transport has been shown to occur before the onset of symptoms in amyotrophic lateral sclerosis (ALS). We have previously shown that several familial ALS-linked copper-zinc superoxide dismutase (SOD1) mutants (A4V, G85R, and G93A) interacted and colocalized with the retrograde dynein-dynactin motor complex in cultured cells and affected tissues of ALS mice. We also found that the interaction between mutant SOD1 and the dynein motor played a critical role in the formation of large inclusions containing mutant SOD1. In this study, we showed that, in contrast to the dynein situation, mutant SOD1 did not interact with anterograde transport motors of the kinesin-1 family (KIF5A, B and C). Using dynein and kinesin accumulation at the sciatic nerve ligation sites as a surrogate measurement of axonal transport, we also showed that dynein mediated retrograde transport was slower in G93A than in WT mice at an early presymptomatic stage. While no decrease in KIF5A-mediated anterograde transport was detected, the slowing of anterograde transport of dynein heavy chain as a cargo was observed in the presymptomatic G93A mice. The results from this study along with other recently published work support that mutant SOD1 might only interact with and interfere with some kinesin members, which, in turn, could result in the impairment of a selective subset of cargos. Although it remains to be further investigated how mutant SOD1 affects different axonal transport motor proteins and various cargos, it is evident that mutant SOD1 can induce defects in axonal transport, which, subsequently, contribute to the propagation of toxic effects and ultimately motor neuron death in ALS.

  • 14.
    Ström, Anna-Lena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)2016Ingår i: Autophagy, ISSN 1554-8627, E-ISSN 1554-8635, Vol. 12, nr 1, s. 1-222Artikel, forskningsöversikt (Refereegranskat)
  • 15.
    Ström, Anna-Lena
    et al.
    University of Kentucky, USA.
    Gal, Jozsef
    Shi, Ping
    Kasarskis, Edward J.
    Hayward, Lawrence J.
    Zhu, Haining
    Retrograde axonal transport and motor neuron disease2008Ingår i: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 106, nr 2, s. 495-505Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Transport of material between extensive neuronal processes and the cell body is crucial for neuronal function and survival. Growing evidence shows that deficits in axonal transport contribute to the pathogenesis of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here we review recent data indicating that defects in dynein-mediated retrograde axonal transport are involved in ALS etiology. We discuss how mutant copper-zinc superoxide dismutase (SOD1) and an aberrant interaction between mutant SOD1 and dynein could perturb retrograde transport of neurotrophic factors and mitochondria. A possible contribution of axonal transport to the aggregation and degradation processes of mutant SOD1 is also reviewed. We further consider how the interference with axonal transport and protein turnover by mutant SOD1 could influence the function and viability of motor neurons in ALS.

  • 16.
    Ström, Anna-Lena
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Hayward, Lawrence J.
    Kasarskis, Edward J.
    Zhu, Haining
    Axonal transport and motor neuron disease2011Ingår i: Cytoskeleton of the Nervous System / [ed] Nixon, Ralph A., Aidong Yuan, New York: Springer-Verlag New York, 2011, s. 529-544Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    Describes cytoskeleton in axonal development and pathology, microtubules and associated proteins, neurofilaments and interacting proteins, actin and its binding proteins, and glial fibrillary acidic protein 2. Focuses on functional significance of neuronal cytoskeleton in axonal transport 3. Encourages further development of unifying principles, stimulates new conceptual and technical approaches toward a better understanding of cytoskeleton functions in health and disease Without a cytoskeleton, a neuron or glial cell would be a shapeless jelly mass unable to function in the milieu of the brain. If we are to understand neuronal cells function in health and disease, we must determine how the cytoskeleton forms and contributes to neural physiology and pathobiology. Cytoskeleton of the Nervous System provides a comprehensive, authoritative and up-to-date account of what we now know and what we want to know in the near future--about the functioning of the cytoskeleton of neuronal cells at the molecular level. In lively accounts, which are unafraid to address controversy, Cytoskeleton of the Nervous System introduces readers to the most sophisticated concepts and latest discoveries: from overexpression systems to knock-out models for specific cytoskeletal proteins, from continuous transport assays in vivo to live-cell imaging in primary neurons, and from factors regulating cytoskeleton behavior to the dysregulation of these processes leading to neurological disease.

  • 17.
    Ström, Anna-Lena
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Shi, Ping
    Zhang, Fujian
    Gal, Jozsef
    Kilty, Renee
    Hayward, Lawrence J
    Zhu, Haining
    Interaction of amyotrophic lateral sclerosis (ALS)-related mutant copper-zinc superoxide dismutase with the dynein-dynactin complex contributes to inclusion formation.2008Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 283, nr 33, s. 22795-805Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    An important consequence of protein misfolding related to neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), is the formation of proteinaceous inclusions or aggregates within the central nervous system. We have previously shown that several familial ALS-linked copper-zinc superoxide dismutase (SOD1) mutants (A4V, G85R, and G93A) interact and co-localize with the dynein-dynactin complex in cultured cells and affected tissues of ALS mice. In this study, we report that the interaction between mutant SOD1 and the dynein motor plays a critical role in the formation of large inclusions containing mutant SOD1. Disruption of the motor by overexpression of the p50 subunit of dynactin in neuronal and non-neuronal cell cultures abolished the association between aggregation-prone SOD1 mutants and the dynein-dynactin complex. The p50 overexpression also prevented mutant SOD1 inclusion formation and improved the survival of cells expressing A4V SOD1. Furthermore, we observed that two ALS-linked SOD1 mutants, H46R and H48Q, which showed a lower propensity to interact with the dynein motor, also produced less aggregation and fewer large inclusions. Overall, these data suggest that formation of large inclusions depends upon association of the abnormal SOD1s with the dynein motor. Whether the misfolded SOD1s directly perturb axonal transport or impair other functional properties of the dynein motor, this interaction could propagate a toxic effect that ultimately causes motor neuron death in ALS.

  • 18.
    Yu, Xin
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Ajayi, Abiodun
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Boga, Narasimha
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Ström, Anna-Lena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Differential degradation of full-length and cleaved ataxin-7 fragments in a novel stable inducible SCA7 model2012Ingår i: Journal of Molecular Neuroscience, ISSN 0895-8696, E-ISSN 1559-1166, Vol. 47, nr 2, s. 219-233Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Spinocerebellar ataxia type 7 (SCA7) is one of nine neurodegenerative disorders caused by expanded polyglutamine repeats, and a common toxic gain-of-function mechanism has been proposed. Proteolytic cleavage of several polyglutamine proteins has been identified and suggested to modulate the polyglutamine toxicity. In this study, we show that full-length and cleaved fragments of the SCA7 disease protein ataxin-7 (ATXN7) are differentially degraded. We found that the ubiquitin-proteosome system (UPS) was essential for the degradation of full-length endogenous ATXN7 or transgenic full-length ATXN7 with a normal or expanded glutamine repeat in both HEK 293T and stable PC12 cells. However, a similar contribution by UPS and autophagy was found for the degradation of proteolytically cleaved ATXN7 fragments. Furthermore, in our novel stable inducible PC12 model, induction of mutant ATXN7 expression resulted in toxicity and this toxicity was worsened by inhibition of either UPS or autophagy. In contrast, pharmacological activation of autophagy could ameliorate the ATXN7-induced toxicity. Based on our findings, we propose that both UPS and autophagy are important for the reduction of mutant ataxin-7-induced toxicity, and enhancing ATXN7 clearance through autophagy could be used as a potential therapeutic strategy in SCA7.

  • 19.
    Yu, Xin
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Muñoz-Alarcón, Andrés
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Ajayi, Abiodun
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Webling, Kristin E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Steinhof, Anne
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Langel, Ülo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Ström, Anna-Lena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Inhibition of Autophagy via p53-Mediated Disruption of ULK1 in a SCA7 Polyglutamine Disease Model2013Ingår i: Journal of Molecular Neuroscience, ISSN 0895-8696, E-ISSN 1559-1166, Vol. 50, nr 3, s. 586-99Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Spinocerebellar ataxia type 7 (SCA7) is one of nine neurodegenerative disorders caused by expanded polyglutamine domains. These so-called polyglutamine (polyQ) diseases are all characterized by aggregation. Reducing the level of aggregating polyQ proteins via pharmacological activation of autophagy has been suggested as a therapeutic approach. However, recently, evidence implicating autophagic dysfunction in these disorders has also been reported. In this study, we show that the SCA7 polyglutamine protein ataxin-7 (ATXN7) reduces the autophagic activity via a previously unreported mechanism involving p53-mediated disruption of two key proteins involved in autophagy initiation. We show that in mutant ATXN7 cells, an increased p53-FIP200 interaction and co-aggregation of p53-FIP200 into ATXN7 aggregates result in decreased soluble FIP200 levels and subsequent destabilization of ULK1. Together, this leads to a decreased capacity for autophagy induction via the ULK1-FIP200-Atg13-Atg101 complex. We also show that treatment with a p53 inhibitor, or a blocker of ATXN7 aggregation, can restore the soluble levels of FIP200 and ULK1, as well as increase the autophagic activity and reduce ATXN7 toxicity. Understanding the mechanism behind polyQ-mediated inhibition of autophagy is of importance if therapeutic approaches based on autophagy stimulation should be developed for these disorders.

  • 20. Zhai, Jianjun
    et al.
    Ström, Anna-Lena
    University of Kentucky, USA.
    Kilty, Renee
    Venkatakrishnan, Priya
    White, James
    Everson, William V.
    Smart, Eric J.
    Zhu, Haining
    Proteomic characterization of lipid raft proteins in amyotrophic lateral sclerosis mouse spinal cord.2009Ingår i: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 276, nr 12, s. 3308-3323Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Familial amyotrophic lateral sclerosis (ALS) has been linked to mutations in the copper/zinc superoxide dismutase (SOD1) gene. The mutant SOD1 protein exhibits a toxic gain-of-function that adversely affects the function of neurons. However, the mechanism by which mutant SOD1 initiates ALS is unclear. Lipid rafts are specialized microdomains of the plasma membrane that act as platforms for the organization and interaction of proteins involved in multiple functions, including vesicular trafficking, neurotransmitter signaling, and cytoskeletal rearrangements. In this article, we report a proteomic analysis using a widely used ALS mouse model to identify differences in spinal cord lipid raft proteomes between mice overexpressing wild-type (WT) and G93A mutant SOD1. In total, 413 and 421 proteins were identified in the lipid rafts isolated from WT and G93A mice, respectively. Further quantitative analysis revealed a consortium of proteins with altered levels between the WT and G93A samples. Functional classification of the 67 altered proteins revealed that the three most affected subsets of proteins were involved in: vesicular transport, and neurotransmitter synthesis and release; cytoskeletal organization and linkage to the plasma membrane; and metabolism. Other protein changes were correlated with alterations in: microglia activation and inflammation; astrocyte and oligodendrocyte function; cell signaling; cellular stress response and apoptosis; and neuronal ion channels and neurotransmitter receptor functions. Changes of selected proteins were independently validated by immunoblotting and immunohistochemistry. The significance of the lipid raft protein changes in motor neuron function and degeneration in ALS is discussed, particularly for proteins involved in vesicular trafficking and neurotransmitter signaling, and the dynamics and regulation of the plasma membrane-anchored cytoskeleton.

  • 21. Zhu, Haining
    et al.
    Zhao, Jun
    Zhu, Beibei
    Collazo, Joanne
    Gal, Jozsef
    Shi, Ping
    Liu, Li
    Ström, Anna-Lena
    University of Kentucky, USA.
    Lu, Xiaoning
    McCann, Richard O.
    Toborek, Michal
    Kyprianou, Natasha
    EMMPRIN regulates cytoskeleton reorganization and cell adhesion in prostate cancer2011Ingår i: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 72, nr 1, s. 72-81Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Proteins on cell surface play important roles during cancer progression and metastasis via their ability to mediate cell-to-cell interactions and navigate the communication between cells and the microenvironment. METHODS: In this study a targeted proteomic analysis was conducted to identify the differential expression of cell surface proteins in human benign (BPH-1) versus malignant (LNCaP and PC-3) prostate epithelial cells. We identified EMMPRIN (extracellular matrix metalloproteinase inducer) as a key candidate and shRNA functional approaches were subsequently applied to determine the role of EMMPRIN in prostate cancer cell adhesion, migration, invasion as well as cytoskeleton organization. RESULTS: EMMPRIN was found to be highly expressed on the surface of prostate cancer cells compared to BPH-1 cells, consistent with a correlation between elevated EMMPRIN and metastasis found in other tumors. No significant changes in cell proliferation, cell cycle progression, or apoptosis were detected in EMMPRIN knockdown cells compared to the scramble controls. Furthermore, EMMPRIN silencing markedly decreased the ability of PC-3 cells to form filopodia, a critical feature of invasive behavior, while it increased expression of cell-cell adhesion and gap junction proteins. CONCLUSIONS: Our results suggest that EMMPRIN regulates cell adhesion, invasion, and cytoskeleton reorganization in prostate cancer cells. This study identifies a new function for EMMPRIN as a contributor to prostate cancer cell-cell communication and cytoskeleton changes towards metastatic spread, and suggests its potential value as a marker of prostate cancer progression to metastasis.

1 - 21 av 21
RefereraExporteraLänk till träfflistan
Permanent länk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf