The mechanisms underlying disease manifestations in neurodegeneration remain unclear, but their understanding is critical to devising effective therapies. We carry out a longitudinal analysis in vivo of identified motoneurons selectively vulnerable (VUL) or resistant (RES) to motoneuron disease (amyotrophic lateral sclerosis, ALS) and show that subtype-selective endoplasmic reticulum (ER) stress responses influence disease manifestations. VUL motoneurons were selectively prone to ER stress and showed gradually upregulated ER stress markers from birth on in three mouse models of familial ALS (FALS). 25–30 days before the earliest denervations, ubiquitin signals increased in both VUL and RES motoneurons, but an unfolded protein response coupled with microglial activation was initiated selectively in VUL motoneurons. This transition was followed by selective axonal degeneration and spreading stress. The ER stress–protective agent salubrinal attenuated disease manifestations and delayed progression, whereas chronic enhancement of ER stress promoted disease. Thus, whereas all motoneurons are preferentially affected in ALS, ER stress responses in specific motoneuron subtypes influence the progressive manifestations of weakening and paralysis.
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We thank J. London (Univ. of Paris 7, France) for generously providing to us the transgenic mice overexpressing wild-type human SOD1. We are grateful to our colleagues S. Arber, B. Roska and D. Schübeler (FMI, Basel) for critically reading the manuscript and providing valuable comments. We thank E. Oakley (FMI, Basel) for valuable assistance with the bioinformatics analysis. S.S. was supported by a grant from the European Union (FP6, Network of Excellence NeuroNE). The Friedrich Miescher Institut is a branch of the Novartis Research Foundation.
The authors have applied for a patent on biomarkers of motoneuron and related neurodegenerative disease under patent application PCT/EP2008/066291.
Supplementary Figures 1–13 and Supplementary Methods (PDF 9285 kb)
P132 G93A-fast mouse treated with vehicle from P30 on (this mouse will die at P136). (MOV 1653 kb)
P132 G93A-fast mouse treated with Salubrinal from P30 on (this mouse will die at P163). (MOV 1659 kb)
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Saxena, S., Cabuy, E. & Caroni, P. A role for motoneuron subtype–selective ER stress in disease manifestations of FALS mice. Nat Neurosci 12, 627–636 (2009). https://doi.org/10.1038/nn.2297
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