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The Journal of Neuroscience, August 5, 2009, 29(31):9903-9917; doi:10.1523/JNEUROSCI.0813-09.2009

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Neurobiology of Disease
A Switch in Retrograde Signaling from Survival to Stress in Rapid-Onset Neurodegeneration

Eran Perlson,¹ Goo-Bo Jeong,² Jenny L. Ross,¹ Ram Dixit,¹ Karen E. Wallace,¹ Robert G. Kalb,² and Erika L. F. Holzbaur¹

¹University of Pennsylvania School of Medicine and ²Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Erika Holzbaur, University of Pennsylvania, D400 Richards Building, 3700 Hamilton Walk, Philadelphia, PA 19104-6085. Email: holzbaur{at}mail.med.upenn.edu

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 SOD1^G93A model. However, similar inhibition is also seen in the Loa and Tg^dynamitin 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 p75^NTR cleavage fragment in the SOD1^G93A 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.

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Received Feb. 16, 2009; revised June 19, 2009; accepted June 26, 2009.

Correspondence should be addressed to Erika Holzbaur, University of Pennsylvania, D400 Richards Building, 3700 Hamilton Walk, Philadelphia, PA 19104-6085. Email: holzbaur{at}mail.med.upenn.edu

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