. A switch in retrograde signaling from survival to stress in rapid-onset neurodegeneration. J Neurosci. 2009 Aug 5;29(31):9903-17. PubMed.


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  1. I think the exciting finding is that while axonal transport is disrupted in several models of motor neuron disease (MND)/amyotrophic lateral sclerosis, this is not the underlying cause of the neurodegeneration. Rather, there is a switch in what cargo is carried. Unfortunately, the death signaling molecules manage to get through, but not those involved in signaling survival. This is a major conceptual advance for the MND field, but it may well have implications for Alzheimer disease (AD) where axonal transport is also disrupted with the development of neurofibrillary tangles. It will be very interesting to see whether there is a similar switch in which molecules get trafficked down axons in AD, and whether this is an explanation for how the pathology (plaques and tangles) result in neurodegeneration.

  2. The paper by Perlson et al. brings to our attention the important issue of the contribution of axonal transport to neuronal pathology, by pointing to a neglected form of axonal transport deficiency. With a mouse model for amyotrophic lateral sclerosis (ALS), Erika Holzbaur’s team shows that, although the axonal transport in these mice is globally perturbed, it is the change in the spectrum of proteins that are being transported that actually inflicts the neuronal pathology.

    The axonal transport powered by kinesins and cytoplasmic dynein ensures the accurate delivery of the functional proteins, including those with a role in signaling, to their specific sites of action. Although the axonal transport in neurons occurs without interruption, the composition of the transported cargo vesicles varies in time according to the changes in the environment and physiological needs. While the overall transport does not normally change (with the transport machinery functioning normally all the time), the delivery of individual signaling proteins, unlike that of housekeeping proteins, fluctuates continuously. Thus, in cases of injury, or some other form of stress, the spectrum of proteins transported in and out of the neurites could change dramatically.

    The paper by Perlson et al. shows that this likely is the case with mouse models of ALS—and probably the human disease, too, where the changes in global transport may be less relevant than the changes in the delivered signals. Although anticipated, this result is hugely important, because it reminds us that the deficiencies in axonal transport of specific proteins, even in the absence of global perturbation of transport, could cause neuronal pathology and neurodegeneration.

    We would like to point at two important things. First, such subtle changes in the transport of a few proteins, on a normal background, may be difficult to detect. Second, this form of modification in axonal transport is not really a deficiency in transport (although it is carried out via transport). Rather, it is a problem of change in protein expression, protein degradation, or—most importantly—protein sorting. Studies will now have to focus more on such aspects, especially on the two major sorting stations for anterograde and retrograde axonal (and dendritic) transport, the trans-Golgi network and the recycling endosome. Thus, analysis of axonal transport in neurodegenerative diseases should also take into consideration changes that occur prior to the transport, at the sorting stations.

    With regard to Alzheimer disease, many studies have focused on global perturbation of axonal transport (e.g., 1,2). However, even in this case, disease-related conditions could change the post-translational processing (e.g., phosphorylation, proteolytic cleavage) of relevant cargo proteins (e.g., the amyloid-β precursor protein). As previously shown, such post-translational modifications could affect sorting into transport vesicles (3), as well as motor recruitment (4). As a consequence, the pattern of APP transport will change. As Erika Holzbaur’s group now clearly shows, axonal transport is a sum of multiple cellular processes that affect the transported proteins in various degrees, under different circumstances.


    . Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta. Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5907-12. PubMed.

    . Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease. Science. 2005 Feb 25;307(5713):1282-8. PubMed.

    . The cleavage products of amyloid-beta precursor protein are sorted to distinct carrier vesicles that are independently transported within neurites. J Neurosci. 2009 Mar 18;29(11):3565-78. PubMed.

    . Coordinated transport of phosphorylated amyloid-beta precursor protein and c-Jun NH2-terminal kinase-interacting protein-1. J Cell Biol. 2005 Nov 21;171(4):615-25. PubMed.

  3. Neurons are unique in that they are highly polarized cells with long projections. Motor neurons have axons that extend from the spinal cord out to the periphery to synapse with muscles; in the case of humans, these axons may extend for over a meter away from the cell body. Active transportation of proteins and organelles along the axon, in both directions between the cell body and the neuron synapse is essential for neuronal survival and communication. Anterograde axonal transport, from cell body to synapse, is undertaken by kinesins and other motor proteins. Retrograde axonal transport, from synapse to the cell body, is driven by the dynein motor within the dynein-dynactin complex.

    Defects in axonal transport have been shown to be present in mouse models of several neurodegenerative diseases, including Huntington disease, Alzheimer disease, and amyotrophic lateral sclerosis (ALS), and pathological findings such as axonal swellings that may be indicative of axonal transport defects have been found in patients with ALS. While mutations in the components of the motor complexes involved in axonal transport can cause neuropathies in humans—for example, defects in p150 dynactin are causal for a form of distal hereditary neuropathy—it has been unclear how much transport deficits contribute to ALS, and in particular we do not know about the effects of disruption of transport of specific cargos in ALS.

    In this landmark paper, Eran Perlson, Erika Holzbaur, and colleagues have assessed retrograde transport and cargoes, and looked at interactions between neurons and glial cells, in mouse models with motor neuron degeneration. The SOD1G93A transgenic mouse carries a human transgene array with a defect in the SOD1 gene that is known to be causative for ALS in humans; this mouse model of human ALS has an aggressive disease profile leading to paralysis and death usually by about three months of age. The Dync1h1Loa (Loa/+) mouse has a defect in the dynein heavy chain, which results in a mild progressive loss of motor neurons (and fairly profound defects in proprioceptive neurons), these mice have a normal lifespan. The Tgdynamitin mice overexpress dynamitin, which results in disruption of the dynein-dynactin complex and slowly progressive motor neuron death.

    Perlson and colleagues have shown that the retrograde transport inhibition in SOD1G93A mice is similar to that observed in both Loa/+ and Tgdynamitin mice, although the dynein motor complex appears to function normally in the ALS model, unlike the latter two mouse strains. In perhaps the most important finding of this exciting paper, the authors have also shown that the nature of the neurotrophin cargoes being transported in SOD1G93A mice is different from those found in wild-type animals. This difference could account for the aggressive motor neuron death seen in the ALS model and the relatively benign deficit seen in Loa/+ mice.

    Perlson, Holzbaur, and colleagues show wild-type mice have retrograde transport of neurotrophic survival factors within motor neurons, whereas in SOD1G93A mice stress/death factors are retrogradely transported in these cells. Importantly, this transport of stress/death factors is already occurring pre-symptomatically (50 days of age) in this ALS model. Another important finding of this paper is that non-neuronal cells such as glia are likely to help mediate this change in signaling. Furthermore, the authors have shown that inhibition of the retrograde stress signaling in motor neuron cultures from SOD1G93A mice was sufficient to inhibit/slow neuronal cell death.

    The results presented in this paper do not identify the primary cause of motor neuron death arising from mutant SOD1. Many changes in cellular homeostasis are observed in SOD1G93A mice, including protein misfolding, aberrant RNA processing, mitochondrial dysfunction, and oxidative stress. Any or many of these changes could contribute to the difference in retrograde transport and signaling in mutant SOD1 mice compared to wild-type animals. Further investigation is required to determine when and what causes retrograde signaling to switch primarily from survival to stress/death signaling, as this may help elucidate what aberrant cellular process(es) kill motor neurons. In addition, work with mouse models always needs to be validated in the human condition, as far as possible. Other interesting questions remain, including whether this profound change in intracellular signaling is specific to SOD1 ALS or is also present in other genetic forms of ALS including that caused by TDP43 and FUS mutations.

    However, this is an extremely important paper for research into motor neuron death, and potentially other neurodegenerative disease, because it highlights the importance of the retrograde signaling cargoes and thus potentially provides a target for therapy. In addition, this paper provides further support to the non-cell-autonomous theory of ALS, whereby changes within motor neurons alone have the ability to cause cell death, but this death is accelerated by interactions with surrounding non-neuronal cells which are also experiencing cellular stress.

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