CNR - Institute of Neuroscience CNR
Institute of Neuroscience
 

Project

Radiation signalling in the nervous system

Radiation signalling in the nervous system

The main focus of the laboratory is on radiation signalling in the nervous system. Radiation therapy has been used for the treatment of tumours for a while. However problems either arise from radiation side effects or from the incurability of tumours being resistant to radiation therapy. In particular, mechanisms mediating radiation resistance are of particular importance. For instance glioblastomas so far are not curable due to the lack of response in terms of apoptosis.

Several factors are conceivable that a tumour cell cannot be killed by g-irradiation or other genotoxic agents. In principle apoptotic resistance can be exerted by extracellular factors like EGF or IGF-1 and their cognate receptors (a) or by altered intracellular signalling mechanisms (b and c).

 

a) Interference with extracellular signalling.
Extracellular ligands like neurotrophins can prevent apoptosis. While for normal development and the maintenance of neurons these factors are crucial, in tumour therapy survival factors may contribute to radiation resistance. Currently we are investigating how IGF-1 interferes with the Atm- p53 apoptosis pathway (figure 1).

b) Interference with intracellular mediated apoptotic resistance.
The cell cycle inhibitor p21Cip1/Waf1 has been shown to be associated with cells being refractory to apoptotic stimuli. Indeed using the mouse cerebellum, we demonstrated that p21Cip1/Waf1 is associated with apoptotic resistance in vivo (Herzog et al., 2002). However, p21Cip1/Waf1 is transcribed also in dying cells. Apparently posttranslational regulation steps using the ubiquitin/proteasome system are involved regarding p21Cip1/Waf1 stability.

Therefore efforts include targeting p21Cip1/Waf1 to degradation in apoptotic resistant cells.

 

c) Cell cycle exit
In cells within the cell cycle p53 is continuously transcribed translated and then degraded by the ubiquitin/proteasome system. After a DNA insult p53 does not get degraded and accumulates in the nucleus. Depending on the cell type either all cells within the cell cycle undergo apoptosis (e.g. neuroblasts of the retina) or cells in G1 and in part in G2 are resistant to DNA damage (like in the cerebellum). These cells are also positive for p21WAF1/Cip1 protein. However when cells exit the cell cycle the p53 system is not activated anymore and cells (e.g. differentiated neurons) survive radiation treatment (figure 2). Therefore one treatment modality could include transferring a tumour cell specifically back to the cell cycle.

 

Prevention of cell death in neurodegenerative diseases

Conversely exuberant cell death like in neurodegenerative diseases needs to be restrained. Often neurodegeneration is mediated by p53. Provided the signalling mechanisms of p53 in cell death are known, this will allow one to interfere with p53 mediated apoptosis. Theoretically like in radiation resistant tumours, p21WAF1/Cip1 can prevent cell death in neurodegenerative diseases. Therefore, a selective stabilization of p21WAF1/Cip1 should prevent apoptosis in vulnerable cells. Moreover since IGF-1 can interfere with the p53 apoptotic pathway the signalling cascades of IGF-1 to the p53 system could be exploited to prevent apoptosis after neurodegenerative insults.

Publications

  • Herzog KH, Chong MJ, Kapsetaki M, Morgan JI, McKinnon PJ (1998) Requirement for Atm in ionizing radiation-induced cell death in the developing central nervous system. Science 280:1089-91.
  • Herzog KH, von Bartheld CS (1998) Contributions of the optic tectum and the retina as sources of brain-derived neurotrophic factor for retinal ganglion cells in the chick embryo. J. Neurosci. 18:2891-906.
  • Braun JS, Herzog KH (2008) E2F1 mediates pneumococcal-induced brain damage. Acta Neuropathol. 116:133-4.
  • Herzog KH, Schulz A, Buerkle C, Gromoll C, Braun JS (2007) Radiation-induced apoptosis in retinal progenitor cells is p53-dependent with caspase-independent DNA fragmentation. Eur. J. Neurosci. 25:1349-56.
  • Mitchell L, Smith SH, Braun JS, Herzog KH, Weber JR, Tuomanen EI (2004) Dual phases of apoptosis in pneumococcal meningitis. J. Infect. Dis. 190:2039-46.
  • Herzog KH, Braun JS, Han SH, Morgan JI (2002) Differential post-transcriptional regulation of p21WAF1/Cip1 levels in the developing nervous system following gamma-irradiation. Eur. J. Neurosci. 15:627-36.
  • Braun JS, Novak R, Herzog KH, Bodner SM, Cleveland JL, Tuomanen EI (1999) Neuroprotection by a caspase inhibitor in acute bacterial meningitis. Nat. Med. 5:298-302.

Grants

The laboratory is sponsored by the Giancarla Vollaro Foundation, Switzerland

 

PI photo

Karl Herzog

Contact information

email  E-mail

email  +39 02 5031 7039

Participating staff
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