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A role for motoneuron subtype–selective ER stress in disease manifestations of FALS mice

Saxena, Smita, Cabuy, Erik, Caroni, Pico·2009·Nature Neuroscience
DOI 10.1038/nn.2297
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Abstract

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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  • Ubiquitin mean fluorescence intensity levels in ventral horn motor neurons are higher in vehicle-treated G93A mice than in compound 2a-treated G93A mice.

    “MFI levels of ubiquitin fluorescence in vehicle-treated G93A MNs were higher than in compound 2a-treated G93A mice, further confirming previous results53 (Fig. 7c and d).”

    From Retromer stabilization results in neuroprotection in a model of Amyotrophic Lateral Sclerosis (2020) · cites this paper as [53]

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Metadata

Authors
Saxena, S., Cabuy, E., & Caroni, P.
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2009-03-29
Volume
12
Issue
5
Pages
627-636
ISSN
  • 1097-6256
  • 1546-1726
DOI
10.1038/nn.2297
Cited by
567
References
7
Language
en
Licence
www.springer.com/tdm (tdm)

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