A switch in retrograde signaling from survival to stress in rapid-onset neurodegeneration

Eran Perlson, Goo Bo Jeong, Jenny L. Ross, Ram Dixit, Karen E. Wallace, Robert G. Kalb, Erika L.F. Holzbaur

Research output: Contribution to journalArticle

138 Scopus citations

Abstract

Retrograde axonal transport of cellular signals driven by dynein is vital for neuronal survival. Mouse models with defects in the retrograde transport machinery, including the Loa mouse (point mutation in dynein) and the Tg dynamitin mouse (overexpression of dynamitin), exhibit mild neurodegenerative disease. Transport defects have also been observed in more rapidly progressive neurodegeneration, such as that observed in the SOD1 G93A transgenic mouse model for familial amyotrophic lateral sclerosis (ALS). Here, we test the hypothesis that alterations in retrograde signaling lead to neurodegeneration. In vivo, in vitro, and live-cell imaging motility assays show misregulation of transport and inhibition of retrograde signaling in the SOD1G93A model. However, similar inhibition is also seen in the Loa and Tgdynamitin mouse models. Thus, slowing of retrograde signaling leads only to mild degeneration and cannot explain ALS etiology. To further pursue this question, we used a proteomics approach to investigate dynein-associated retrograde signaling. These data indicate a significant decrease in retrograde survival factors, including P-Trk (phospho-Trk) and P-Erk1/2, and an increase in retrograde stress factor signaling, including P-JNK (phosphorylated c-Jun N-terminal kinase), caspase-8, and p75NTR cleavage fragment in the SOD1G93A model; similar changes are not seen in the Loa mouse. Cocultures of motor neurons and glia expressing mutant SOD1 (mSOD1) in compartmentalized chambers indicate that inhibition of retrograde stress signaling is sufficient to block activation of cellular stress pathways and to rescue motor neurons from mSOD1-induced toxicity. Hence, a shift from survival-promoting to death-promoting retrograde signaling may be key to the rapid onset of neurodegeneration seen in ALS.

Original languageEnglish (US)
Pages (from-to)9903-9917
Number of pages15
JournalJournal of Neuroscience
Volume29
Issue number31
DOIs
StatePublished - Aug 5 2009
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)

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    Perlson, E., Jeong, G. B., Ross, J. L., Dixit, R., Wallace, K. E., Kalb, R. G., & Holzbaur, E. L. F. (2009). A switch in retrograde signaling from survival to stress in rapid-onset neurodegeneration. Journal of Neuroscience, 29(31), 9903-9917. https://doi.org/10.1523/JNEUROSCI.0813-09.2009