Neuronal Apoptosis

Culmsee Lab

phone: +49 (0)6421-28-25780 email: carsten.culmsee@staff.uni-marburg.de

We are investigating mechanisms of neuronal cell death and neuroinflammation in experimental models relevant for cerebral ischemia and neurodegenerative diseases (M. Alzheimer, M. Parkinson). Current projects focus on mitochondrial mechanisms of apoptosis and necroptosis, and related generation of reactive oxygen species and calcium deregulation in neurons. Pharmacological approaches target mitochondrial fission and fusion, potassium channels and the regenerative potential of stem cells.
Research

Mechanisms of neuronal cell death and brain damage

  • Pathogenetic mechanisms in neurodegenerative diseases (stroke, Alzheimer’s disease, epileptic seizures, brain trauma)
  • Neuronal apoptosis: initial molecular signaling pathways and gene expression
  • Mitochondrial mechanisms of neuronal cell death
  • Generation of reactive oxygen species (ROS) and oxidative stress-related signaling
  • DNA damage-induced signalling pathways
  • Caspase-independent Apoptosis; Apoptosis inducing factor (AIF)
  • Cellular mechanisms of brain damage: disturbance of the neurovascular unit and related inflammatory processes

Mechanisms of neuroprotection

  • Inhibition of pro-apoptotic bcl-2 family proteins
  • Protection of mitochondrial function
  • Inhibition of AIF-mediated cell death signalling
  • Neuroprotection by p53-inhibitors
  • Activation of endogenous pathways of neuroprotection by activation of NF-kappa B
  • Inhibition of oxidative stress and related signalling pathways
  • Vector systems for efficient siRNA delivery to the CNS

Experimental techniques

  • Primary cultures of hippocampal and cortical neurons (mice, rats), cell lines (HT-22 cells, PC12 cells)
  • Models of neuronal cell death relevant for neurodegenerative diseases
  • Immunhistochemistry, immuncytochemistry, ELISA, immunoblots, immunprecipitation, confocal laser scanning microscopy
  • RT-PCR, TUNEL, antisense oligonucleotides; RNAi-technology
  • Evaluation of mitochondrial function and levels of reactive oxygen species by using fluorescent dyes
  • Confocal microscopy of cultured neurons, time lapse in vivo imaging
  • Electromobilityshift assays (NF-kB, p53)
  • Enzyme activity assays
  • Animal models of cerebral ischemia (mice, rats)
  • Stereotactic intracerebral injections/infusions
    siRNA vectors
Selected Publications
  • Dolga AM, Letsche T, Gold M, Doti N, Bacher M, Chiamvimonvat N, Dodel R, Culmsee C (2012) Activation of KCNN3/SK3/K(Ca)2.3 channels attenuates enhanced calcium influx and inflammatory cytokine production in activated microglia. Glia 60(12): 2050-64
  • Grohm J, Kim SW, Mamrak U, Tobaben S, Cassidy-Stone A, Nunnari J, Plesnila N, Culmsee C (2012) Inhibition of Drp1 provides neuroprotection in vitro and in vivo. Cell Death Differ 19(9):1446-58
  • Tobaben S, Grohm J, Seiler A, Conrad M, Plesnila N, Culmsee C (2011) Bid-mediated mitochondrial damage is a key mechnism in glutamate-induced oxidative stress and AIF-dependent cell death in immortalized HT-22 hippocampal neurons. Cell Death and Differentiation 18(2):282-292
  • Hangen E, De Zio D, Bordi M, Zhu C, Dessen P, Caffin F, Lachkar S, Perfettini JL, Lazar V, Benard J, Fimia GM, Piacentini M, Harper F, Pierron G, Vicencio JM, Bénit P, de Andrade A, Höglinger G, Culmsee C, Rustin P, Blomgren K, Cecconi F, Kroemer G, Modjtahedi N (2010) A brain-specific isoform of mitochondrial apoptosis-inducing factor: AIF2.Cell Death Differ. 17(7):1155-66
  • Seiler A, Schneider M, Förster H, Roth S, Wirth EK, Culmsee C, Plesnila N, Kremmer E, Rådmark O, Wurst W, Bornkamm GW, Schweizer U, Conrad M (2008) Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab. 2008 Sep;8(3):237-48.
  • Landshamer S, Hoehn M, Barth N, Duvezin-Caubert S, Schwake G, Tobaben S, Kazhdan I, Becattini B, Zahler S, Vollmar A, Pellecchia M, Reichert A, Plesnila N, Wagner E, Culmsee C (2008) Bid-induced release of AIF from mitochondria causes immediated neuronal cell death. Cell Death Differ. 2008 Oct;15(10):1553-63
  • Plesnila N, von Baumgarten L, Retiounskaia M, Engel D, Ardeshiri A, Zimmermann R, Hofmann F, Landshamer S, Wagner E, Culmsee C (2007). Delayed neuronal death after brain trauma involves p53-dependent inhibition of NF-kB transcriptional activity. Cell Death Diff., 14: 1529-1541.