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Published online 3 May 2004. doi:10.1083/jcb.200403028
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 165, Number 3, 357-369
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Article

 ERK activation promotes neuronal degeneration predominantly through plasma membrane damage and independently of caspase-3

Srinivasa Subramaniam1, Ute Zirrgiebel2, Oliver von Bohlen und Halbach1, Jens Strelau1, Christine Laliberté4, David R. Kaplan3,4, and Klaus Unsicker1

1 Neuroanatomy and Interdisciplinary Center for Neurosciences, University of Heidelberg, D-69120 Heidelberg, Germany
2 Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada
3 Department of Medical Genetics and Microbiology and Institute of Medical Sciences, University of Toronto, Toronto, Ontario M5S 1A8, Canada
4 The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada

Address correspondence to S. Subramaniam, Neuroanatomy and Interdisciplinary Center for Neurosciences, University of Heidelberg, Im Neuenheimer Feld 307, 2. OG, D-69120 Heidelberg, Germany. Tel.: 49 6221 54 8304. Fax: 49 6221 54 5604. email: Srinivasa.Subramaniam{at}urz.uni-heidelberg.de

Our recent studies have shown that extracellular-regulated protein kinase (ERK) promotes cell death in cerebellar granule neurons (CGN) cultured in low potassium. Here we report that the "death" phenotypes of CGN after potassium withdrawal are heterogeneous, allowing the distinction between plasma membrane (PM)–, DNA-, and PM/DNA-damaged populations. These damaged neurons display nuclear condensation that precedes PM or DNA damage. Inhibition of ERK activation either by U0126 or by dominant-negative mitogen-activated protein kinase/ERK kinase (MEK) overexpression results in a dramatic reduction of PM damaged neurons and nuclear condensation. In contrast, overexpression of constitutively active MEK potentiates PM damage and nuclear condensation. ERK-promoted cellular damage is independent of caspase-3. Persistent active ERK translocates to the nucleus, whereas caspase-3 remains in the cytoplasm. Antioxidants that reduced ERK activation and PM damage showed no effect on caspase-3 activation or DNA damage. These data identify ERK as an important executor of neuronal damage involving a caspase-3–independent mechanism.

Key Words: DNA damage; apoptosis; necrosis; MAPK; antioxidants

The online version of this article includes supplemental material.

Abbreviations used in this paper: Ac-DEVD-CHO, acetyl-Asp-Glu-Val-Asp-aldehyde; CA, constitutively active; CGN, cerebellar granule neuron; CHX, cyclohexamide; CN, condensed nuclei; DN, dominant-negative; Egr-1, early growth response gene-1; ERK, extracellular-regulated protein kinase; JNK, c-Jun NH2-terminal kinase; MEK, MAPK/ERK kinase; MOI, multiplicity of infection; N-AC, N-acetyl cysteine; pERK, persistent active ERK; PI, propidium iodide; PM, plasma membrane; ROS, reactive oxygen species; SOD, superoxide dismutase; Z-VAD-FMK, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone.


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