Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL

doi:10.1073/pnas.0508774103

Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL

*Ecole Polytechnique Fédérale de Lausanne (EPFL), Integrative Biosciences Institute, SV IBI LEN, AAB 1 32, CH-1015 Lausanne, Switzerland;
^†Institut de Neurobiologie de la Méditerranée (INMED), Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe Avenir, F-13273 Marseille Cedex 09, France;
^‡Université de la Méditerranée, F-13288 Marseille, France; and
^§Institut de Biologie du Développement de Marseille (IBDM), Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche 623, F-13288 Marseille Cedex 09, France

Edited by Fred H. Gage, The Salk Institute for Biological Studies, San Diego, CA, and approved February 14, 2006 (received for review October 10, 2005)

Abstract

The reasons for the cellular specificity and slow progression of motoneuron diseases such as ALS are still poorly understood. We previously described a motoneuron-specific cell death pathway downstream of the Fas death receptor, in which synthesis of nitric oxide (NO) is an obligate step. Motoneurons from ALS model mice expressing mutant SOD1 showed increased susceptibility to exogenous NO as compared with controls. Here, we report a signaling mechanism whereby NO leads to death of mutant, but not control, motoneurons. Unexpectedly, exogenous NO triggers expression of Fas ligand (FasL) in cultured motoneurons. In mutant SOD1^G93A and SOD1^G85R, but not in control motoneurons, this up-regulation results in activation of Fas, leading through Daxx to phosphorylation of p38 and further NO synthesis. This Fas/NO feedback amplification loop is required for motoneuron death in vitro. In vivo, mutant SOD1^G93A and SOD1^G85R mice show increased numbers of positive motoneurons and Daxx nuclear bodies weeks before disease onset. Moreover, FasL up-regulation is reduced in the presence of transgenic dominant-negative Daxx. We propose that chronic low-level activation of the Fas/NO feedback loop may underlie the motoneuron loss that characterizes familial ALS and may help to explain its slowly progressive nature.

Footnotes

^‖To whom correspondence should be addressed at:
Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Neurobiologie de la Méditerranée (INMED), Equipe Avenir, F-13273 Marseille Cedex 09, France.
E-mail: haase{at}inmed.univ-mrs.fr
↵ ^¶Present address: Departments of Pathology and Neurology, Columbia University, New York, NY 10032.
Author contributions: C.R., P.A., B.P., C.E.H., and G.H. designed research; C.R., E.B., C.S., A.J., B.P., and G.H. performed research; G.H. contributed new reagents/analytic tools; C.R., E.B., B.P., and G.H. analyzed data; and C.R., C.E.H., and G.H. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Abbreviations:

DIV,

day(s) in vitro;

NB,

nuclear bodies.