Differentiation and identification of cell death components in mouse-mutants with multiple neuronal degeneration.


Activation of the ubiquituous enzyme-cascades of the caspase-family is possible by a multitude of intrinsic and extrinsic signals and leads to a mode of "organized" cell death called apoptosis. The identification of activated factors of these cascades in neurodegenerative diseases in man indicates a role for apoptotic mechanisms in the course of these disorders. However, blocking of these factors is unable to influence the progression of cell death sufficiently, even in those disorders in which cell death signalling has been almost completely revealed (e.g. M. Parkinson). This therapeutic ineffectiveness is likely due to a parallel activation of alternative cell death pathways. Caused by this redundancy, a defect acting identically on various cell populations, may activate different cascades in the diverse populations. In the mouse mutants weaver and Lurcher, the respective defects act identically on different neuronal populations. Single base-pair substitutions in a K+-channel- and a glutamate receptor-gene, respectively, lead to the chronic depolarization and the subsequent degeneration of neurons in the cerebellum, the brainstem and the substantia nigra. Using new cell death markers and identifying intermediate cell-death factors, it is the purpose of this project to reveal common and different features in the cell-death pathways in the various neuronal populations affected in these mutants, and to relate them to their functional and topographic context.
Head of Project:

Dr. Jörg Bäurle
Charité - Universitätsmedizin Berlin
Institute of Physiology CBF
Tel. 8445 1675
Fax 8445 1602
joerg.baeurle@charite.de
Additional Member of Project:

Dr. Sabine Frischmuth, Heidi Wolynski
Begin/End of Project:

01/2005- 12/2005
Funded by:

Universitäre Forschungsförderung Charité
Publications:

Zuo, J., DeJager, P.L., Takahashi, K.A., Jiang, W., Linden, D.J., Heintz, N. (1997): Neurodegeneration in Lurcher mice caused by mutation in 2 glutamate receptor gene. Nature 288, 769-733. Mattson, M.P. (2000): Apoptosis in neurodegenerative disorders. Nat. Rev. Mol. Cell Biol. 1, 120-129. RADNIKOW, G., TITZ, S., MADES, S., BÄURLE, J., MISGELD, U. (2001) Impaired GABAB receptor-mediated inhibition in pars compacta neurons of the weaver substantia nigra. Neurosci. Lett. 299:81-84. GRÜSSER-CORNEHLS, U., BÄURLE, J. (2001) Mutant mice as a model for cerebellar ataxia. Prog. Neurobiol. 63:489-540. BÄURLE, J., FRISCHMUTH, S., KRANDA, K. (2004) TRAIL-related death receptors in normal, Lurcher and weaver mutant mouse brain. Neurosci. Lett. 372/1-2:46-51.