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The amyloid precursor protein potentiates CHOP induction and cell death in response to ER Ca2+ depletion
(2007)
- Poster presentation: Here we investigated the role of the amyloid precursor protein (APP) in regulation of Ca2+ store depletion-induced neural cell death. Ca2+ store depletion from the endoplasmic reticulum (ER) was induced by the SERCA (Sarco/Endoplasmic Reticulum Calcium ATPase) inhibitor thapsigargin which led to a rapid induction of the unfolded protein response (UPR) and a delayed activation of executioner caspases in the cultures. Overexpression of APP potently enhanced cytosolic Ca2+ levels and cell death after ER Ca2+ store depletion in comparison to vector-transfected controls. GeneChipR and RT-PCR analysis revealed that the expression of classical UPR chaperone genes was not altered by overexpression of APP.Interestingly, the induction of the ER stress-responsive pro-apoptotic transcription factor CHOP was significantly upregulated in APP-overexpressing cells in comparison to vectortransfected controls. Chelation of intracellular Ca2+ with BAPTA-AM revealed that enhanced CHOP expression after store depletion occured in a Ca2+-dependent manner in APPoverexpressing cells. Prevention of CHOP induction by BAPTA-AM and by RNA interference was also able to abrogate the potentiating effect of APP on thapsigargin-induced apoptosis. Application of the store-operated channel (SOC)-inhibitors SK F96365 and 2-APB downmodulated APP-triggered potentiation of cytosolic Ca2+ levels and apoptosis after treatment with thapsigargin. Our data demonstrate that APP-mediated regulation of ER Ca2+ homeostasis significantly modulates Ca2+ store depletion-induced cell death in a SOC- and CHOP-dependent manner, but independent of the UPR.
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Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration
(2009)
- Background Parkinson's disease (PD) is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD. Methodology/Principal Findings Now we generated a PINK1 deficient mouse and observed several novel phenotypes: A progressive reduction of weight and of locomotor activity selectively for spontaneous movements occurred at old age. As in PD, abnormal dopamine levels in the aged nigrostriatal projection accompanied the reduced movements. Possibly in line with the PARK6 syndrome but in contrast to sporadic PD, a reduced lifespan, dysfunction of brainstem and sympathetic nerves, visible aggregates of alpha-synuclein within Lewy bodies or nigrostriatal neurodegeneration were not present in aged PINK1-deficient mice. However, we demonstrate PINK1 mutant mice to exhibit a progressive reduction in mitochondrial preprotein import correlating with defects of core mitochondrial functions like ATP-generation and respiration. In contrast to the strong effect of PINK1 on mitochondrial dynamics in Drosophila melanogaster and in spite of reduced expression of fission factor Mtp18, we show reduced fission and increased aggregation of mitochondria only under stress in PINK1-deficient mouse neurons. Conclusion Thus, aging Pink1 -/- mice show increasing mitochondrial dysfunction resulting in impaired neural activity similar to PD, in absence of overt neuronal death.
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Literatur im Netz - Sammeln, Erschließen, Archivieren. Praxisbericht über eine neue Herausforderung für die klassische Bibliothek. Vortrag auf der ASpB-Tagung an der Universitätsbibliothek Karlsruhe am 23.09.2009
(2009)
- In seinen Sammlungen bildet das Deutsche Literaturarchiv Marbach (DLA) das Netzwerk des literarischen Lebens in all seinen Facetten ab. Im Zentrum des quellenorientierten Sammelns und der Erschließung steht der Autor (bzw. die Autorin). Die Literatur wird dokumentiert vom Entstehungsprozess eines Werkes über die verschiedenen Ausgaben und dessen Rezeption in der Literaturkritik, seine dramaturgische Umsetzung in Hörfunk, Film, auf der Bühne und in der Musik. Seit 2008 bezieht das DLA auch Internetquellen wie literarische Zeitschriften, Netzliteratur und Weblogs in sein Spektrum mit ein und reagiert damit auf die zunehmende Bedeutung des Internets als Publikationsforum. Sammeln, Erschließen und Archivieren bilden eine notwendige Einheit; gerade die Flüchtigkeit der netzbasierten Ressourcen macht eine langfristige Sicherung der Verfügbarkeit erforderlich. Notwendig sind daher mehrere Säulen, auf denen diese neue Sammlung von „Literatur im Netz“ basiert.
