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

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 Tgdynamitin 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 SOD1G93A transgenic mouse model for familial 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 mis-regulation 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 and P-Erk1/2, and an increase in retrograde stress factor signaling, including P-JNK, Caspase-8 and p75NTR cleavage fragment in the SOD1G93A model; similar changes are not seen in the Loa mouse. Co-cultures 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.

Axonal transport deficits and degeneration can evolve independently in mouse models of amyotrophic lateral sclerosis

“…Hence, axonal transport of organelles might not be a suitable target to therapeutically prevent the irreversible loss of neurons or axons in ALS, although in other neurodegenerative diseases, this might clearly be a promising strategy (34). However, our study does not exclude disturbances in slow axonal transport (35,36) or changes in cargo composition (27) as important steps in ALS pathogenesis, and does not contradict the view that organelle transport deficits can accelerate axon degeneration, e.g., in the SOD G93A model (25). Moreover, our argument strictly applies only to mitochondria and endosome-derived vesicles.…”

“…The aim of our study was to investigate the in vivo consequences of reduced organelle transport in ALS mice, which-based on the published literature (7,8,16,26,27)-we expected to be a general feature of ALS disease models. However, when we compared several different bona fide models of SOD-based familial ALS, we found to our surprise that rather than cosegregating with the ALS-specific mutation, transport disturbances were only present in some SOD overexpression models (G93A, G37R, and wildtype SOD, but not G85R), irrespective of whether the enzyme carried an ALS mutation.…”

“…Indeed, there is further evidence that argues against a direct role of organelle transport deficits in causing the degenerative phenotype in SOD G93A mice, because increasing mitochondrial transport does not yield the expected therapeutic benefit in SOD G93A mice (33). Furthermore, although the fact that mutations in motor proteins can cause a neurodegenerative phenotype is often cited in support of a role for axonal transport in ALS pathogenesis, mutations in retrograde motor proteins alone do not phenocopy SOD G93A (27). Still, although not primarily pathogenic, the motor axon-specific transport deficits-as seen in SOD G93A or SOD G37R mice-might contribute to the phenotypic variations found between the diseases caused by differentially mutated SOD.…”

Deficits in axonal transport precede ALS symptoms in vivo

“…Consistently, several lines of evidence suggest that deficits in both anterograde and retrograde transport contribute to ALS pathogenesis (3,4,10,(15)(16)(17)(18)(19)(20)(21)(22)(23). ALS patients and mice expressing mutant superoxide dismutase 1 (SOD1) display neurofilament accumulations, which may derive from defects in slow anterograde transport (19,24,25).…”

DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury

“…As axon injury may occur a significant distance from the cell body, it has been proposed that retrograde molecular motors play a critical role in conveying damage signals to the nucleus, allowing the cell to respond to damage (3). Attenuation of this transport mechanism has been shown to reduce degeneration, suggesting that the ability of the nucleus to detect an insult is an essential component of the injury response (4).…”