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Challenge of Neuroscience against Amyotrophic Lateral Sclerosis

開催日 2014/9/12
時間 9:00 - 11:00
会場 Room E(301)
Chairperson(s) 永井 真貴子 / Makiko Nagai (北里大学医学部 神経内科 / Department of Neurology, Kitasato University, Japan)
横田 隆徳 / Takanori Yokota (東京医科歯科大学大学院脳神経病態学 / Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Japan)

ALS astrocytes kill motor neurons via ligation of death receptor 6 by a fragment of N-APP/APLP1

  • S2-E-1-4
  • Diane Re:1 Virginia Le Verche:1 Mariano Alvarez:1 Dimitra Papadimitriou:1 Tetsuya Nagata:1 Andrea Califano:1 Harry Ishiropoulos:2 Manuel Than:3 Marc Tessier-Lavigne:4 Serge Przedborski:1 
  • 1:Columbia University, USA 2:The Children's Hospital of Philadelphia, USA 3:Leibniz Institute for Age Research, Leipzig, Germany 4:Rockefeller University, NY, USA 

Mutations in superoxide dismutase-1 (SOD1) cause a form of amyotrophic lateral sclerosis (ALS). Previously, we showed that embryonic stem cell-derived (ES-) motor neurons (MNs) are killed by mutated SOD1-expressing astrocytes or their conditioned medium (CM) (Nagai et al., 2007). Here we show that the deleterious effect of mutant astrocytes is mediated by a negatively charged protein of ~5-30 kDa, which might be a ligand to MN cell surface transduction protein. By liquid chromatography-mass spectrometry analysis, we found a list of 121 potential ligands selectively enriched in, or unique to the toxic mutant astrocyte CM. To identify within this list the extracellular toxic ligand and its associated cell surface transducer, we adopted a non- bias genome-wide approach. Purified ES-MNs were exposed for 72 hours to ALS astrocyte CM and analyzed by RNA-seq. From these gene expression data, differential protein activity was inferred through a regulatory network-based approach. We found significant changes in activity for 84 membrane proteins. Based on protein-protein interaction knowledge we ended up with 5 couples of putative receptor/ligand that we have systematically tested in our models. We found that the genetic ablation of the second most activated receptor, death receptor 6 in the MN compartment was fully protective. In agreement, the mirror ablation in the astrocytes of amyloid beta precursor protein (APP) or of amyloid precursor-like protein 1 (APLP1), two potential ligands of this receptor, also completely reversed MN death. We also found that recombinants of N-term APP and APLP1 were toxic to MNs in a DR6-dependent manner. Thus, the present study reports on a new neuroglial disease mechanism which could open new promising therapeutic avenues for this common, incurable disease.

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