J Lewerenz

Publications (7)25.98 Total impact

• Article: The plasma membrane channel ORAI1 mediates detrimental calcium influx caused by endogenous oxidative stress.

  N Henke, P Albrecht, I Bouchachia, M Ryazantseva, K Knoll, J Lewerenz, E Kaznacheyeva, P Maher, A Methner
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  ABSTRACT: The mouse hippocampal cell line HT22 is an excellent model for studying the consequences of endogenous oxidative stress. Addition of extracellular glutamate depletes the cells of glutathione (GSH) by blocking the glutamate-cystine antiporter system x(c)(-). GSH is the main antioxidant in neurons and its depletion induces a well-defined program of cell death called oxytosis, which is probably synonymous with the iron-dependent form of non-apoptotic cell death termed ferroptosis. Oxytosis is characterized by an increase of reactive oxygen species and a strong calcium influx preceding cell death. We found a significant reduction in store-operated calcium entry (SOCE) in glutamate-resistant HT22 cells caused by downregulation of the Ca(2+) channel ORAI1, but not the Ca(2+) sensors STIM1 or STIM2. Pharmacological inhibition of SOCE mimicked this protection similarly to knockdown of ORAI1 by small interfering RNAs. Long-term calcium live-cell imaging after induction of the cell death program showed a specific reduction in Ca(2+)-positive cells by ORAI1 knockdown. These results suggest that dysregulated Ca(2+) entry through ORAI1 mediates the detrimental Ca(2+) entry in programmed cell death induced by GSH depletion. As this detrimental Ca(2+) influx occurs late in the course of the cell death program, it might be amenable to therapeutic intervention in diseases caused by oxidative stress.
  Cell Death & Disease 01/2013; 4:e470. · 5.33 Impact Factor
• Article: Mutation of ATF4 mediates resistance of neuronal cell lines against oxidative stress by inducing xCT expression.

  J Lewerenz, H Sato, P Albrecht, N Henke, R Noack, A Methner, P Maher
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  ABSTRACT: Selecting neuronal cell lines for resistance against oxidative stress might recapitulate some adaptive processes in neurodegenerative diseases where oxidative stress is involved like Parkinson's disease. We recently reported that in hippocampal HT22 cells selected for resistance against oxidative glutamate toxicity, the cystine/glutamate antiporter system x(c)(-), which imports cystine for synthesis of the antioxidant glutathione, and its specific subunit, xCT, are upregulated. (Lewerenz et al., J Neurochem 98(3):916-25). Here, we show that in these glutamate-resistant HT22 cells upregulation of xCT mediates glutamate resistance, and xCT expression is induced by upregulation of the transcription factor ATF4. The mechanism of ATF4 upregulation consists of a 13 bp deletion in the upstream open reading frame (uORF2) overlapping the ATF4 open reading frame. The resulting uORF2-ATF4 fusion protein is efficiently translated even at a low phosphorylation levels of the translation initiation factor eIF2α, a condition under which ATF4 translation is normally suppressed. A similar ATF4 mutation associated with prominent upregulation of xCT expression was identified in PC12 cells selected for resistance against amyloid β-peptide. Our data indicate that ATF4 has a central role in regulating xCT expression and resistance against oxidative stress. ATF4 mutations might have broader significance as upregulation of xCT is found in tumor cells and associated with anticancer drug resistance.
  Cell death and differentiation 11/2011; 19(5):847-58. · 8.24 Impact Factor
• Article: Successful immunosuppressive treatment and long-term follow-up of anti-Ri-associated paraneoplastic myelitis.

  F Leypoldt, P Eichhorn, C Saager, A Münchau, J Lewerenz
  Journal of neurology, neurosurgery, and psychiatry 11/2006; 77(10):1199-200. · 4.87 Impact Factor
• Article: Multiple vascular abnormalities and a paradoxical combination of vitamin B12 deficiency and thrombocytosis in a case with POEMS syndrome.

  J Lewerenz, A Gocht, P H Hoeger, P von den Driesch, B Eckert, K Lamszus, H-J Stuerenburg, A Methner
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  ABSTRACT: POEMS/Crow-Fukase syndrome is a rare multisystem disorder associated with elevated vascular endothelial growth factor (VEGF), which clinically presents with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes. We report a case of POEMS syndrome due to a gammopathy of undetermined significance with thrombocytosis, vitamin B(12) deficiency, highly elevated VEGF and in addition to glomeruloid angiomas two previously undescribed proliferative vascular lesions: a spinal arteriovenous fistula and a plexogenic pulmonary arteriopathy, which ultimately resulted in lethal pulmonary hypertension. We assume that the high VEGF levels caused the vascular abnormalities observed in our patient.
  Journal of Neurology 01/2004; 250(12):1488-91. · 3.47 Impact Factor
• Article: Identification of genes up-regulated by retinoic-acid-induced differentiation of the human neuronal precursor cell line NTERA-2 cl.D1.

  F Leypoldt, J Lewerenz, A Methner
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  ABSTRACT: The human teratocarcinoma cell line NTERA-2 cl.D1 (NT2 cells) can be induced with retinoic acid and cell aggregation to yield postmitotic neurones. This seems to model the in vivo situation, as high concentrations of retinoic acid, retinoic acid binding proteins, and receptors have been detected in the embryonic CNS and the developing spinal cord suggesting a role for retinoic acid in neurogenesis. Suppression subtractive hybridization was used to detect genes up-regulated by this paradigm of neuronal differentiation. Microfibril-associated glycoprotein 2 was found to be drastically up-regulated and has not been implicated in neuronal differentiation before. Suppression subtractive hybridization also identified DYRK4, a homologue of the Drosophila gene minibrain. Minibrain mutations result in specific defects in the development of the fly central nervous system. In adult rats, DYRK4 is only expressed in testis, but our results suggest an additional role for DYRK4 in neuronal differentiation. We have shown that suppression subtractive hybridization in conjunction with an efficient screening procedure is a valuable tool to produce a repertoire of differentially expressed genes and propose a new physiological role for several identified genes and expressed sequence tags.
  Journal of Neurochemistry 03/2001; 76(3):806-14. · 4.06 Impact Factor
• Article: [School sports--early prevention of coronary heart disease?].

  E O Krasemann, J Lewerenz
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  ABSTRACT: In its usual form, school sports is neither calculated to motivate a lifelong pursuance of sports, nor is it particularly suitable for primary prevention of coronary heart disease. In view of the multifactorial pathogenetic nature of this disease, school sports can be nothing more than an adjunctive prophylactic measure. Epidemiological studies have shown a high level of probability for the usefulness of physical exercise as a preventive measure in childhood and adolescence. However, the findings of sports-medical research on endurance sports must be taken into account. In a controlled study of Hamburg children covering a period of 3 years, it was shown that pupils with high self-esteem, which was particularly encouraged, have better pre-conditions for a lifelong interest in active sports.
  Fortschritte der Medizin 07/1989; 107(17):375-7.
• Article: [Coronary heart disease--prevention in school].

  E O Krasemann, J Lewerenz
  Fortschritte der Medizin 05/1986; 104(16):331-5.