Mitochondria hobble along the motor neuron axons as those axons degenerate in amyotrophic lateral sclerosis—yet the limping organelles and the dying back of the axons are discrete events, according to a report February 27 in the Proceedings of the National Academy of Sciences online. Examining three genetic mouse models for ALS, the study authors determined that, while the mitochondria dally before axons shrivel in the most commonly used lab mouse, in another model the axons succumb even while mitochondria still bustle along unaffected. Previous research suggested mitochondrial transport deficits might kick start ALS pathology. The report provides an important lesson, said senior author Thomas Misgeld of the Technical University Munich, Germany, in that scientists must examine several ALS models to obtain a complete story about pathology.

The work is well done, commented Giovanni Manfredi of the Weill Cornell Medical College of Cornell University in New York City, but he questioned the interpretations. Just because axonal degeneration does not follow hot on the heels of mitochondrial defects does not mean the two are unrelated, said Manfredi, who also works on mitochondria in ALS (see ARF related news story). Neuron death is likely the result of small insults having built up over time, Manfredi said, and mitochondrial problems could still be one of those insults.

Misgeld and others noted that mitochondria are but one among many kinds of axonal cargo that might be affected in this disease. “Transport disturbances in ALS are by no means ‘out’ by our study,” Misgeld said. “We cannot generalize…for all cargoes.” Misgeld led the work with co-senior author Martin Kerschensteiner of Ludwig Maximilians University Munich and first author Petar Marinkovic at Technical University Munich.

Altered axonal transport has been linked to several neurodegenerative conditions (see ARF related news story; De Vos et al., 2008), including Alzheimer’s (see ARF related news story on Stokin et al., 2005), Huntington’s (see ARF related news story on Szebenyi et al., 2003), and ALS (De Vos et al., 2007). “However, whether the abnormal axonal transport is a cause, a contributing factor, or simply a consequence of the neuronal pathology is still an open question,” wrote Virgil and Zoia Muresan of the University of Medicine and Dentistry of New Jersey in Newark in an e-mail to ARF (see full comment below).

Marinkovic and colleagues addressed the question in model mice overexpressing the human ALS gene superoxide dismutase 1. “Considering the body of previously published data—strongly suggesting that the transport of mitochondria deteriorates prior to neurodegeneration and likely causes the synaptic alterations in motor neurons—their results are somewhat surprising,” the Muresans wrote (see ARF related news story on Magrané et al., 2012).

Misgeld, Kerschensteiner, and colleagues followed mitochondrial dynamics in neuron preparations from live mice (Misgeld et al., 2007). Marinkovic explanted chest muscle, along with its attendant nerves, for study under the microscope. He crossed the mSOD1 mice with a line carrying a transgene driving expression of a fluorescent protein in neuronal mitochondria. The photo-convertible marker, called Kaede, starts out emitting green but changes to red when hit with violet light. By converting a few mitochondria to red, Marinkovic could watch their progress as they traveled in a sea of green peers.

First, Marinkovic examined mitochondrial trafficking in the popular SOD1-G93A model. These mice tend to exhibit denervation of muscles and clinical symptoms around three to four months of age. As seen by other researchers (Bilsland et al., 2010), transport defects arose first—before the animals reached three weeks old, Misgeld said. Compared to mitochondria from wild-type control mice, the SOD1-G93A organelles moved more slowly, paused more often, and stayed put for longer periods. The results were similar for another model, SOD1-G37R mice.

There are two possible interpretations of these results, Misgeld said. For one, it might be that the negative effects of the mitochondrial transport defect build up, over months, to a point when the axons finally shrivel. Alternatively, he said, perhaps the two events are not closely related after all.

To investigate further, the scientists repeated the experiment in SOD1-G85R mice. These mice survive for nearly a year. The team was surprised to see that mitochondrial traffic patterns remained mostly normal even up to the age the animals were near death. This suggested to them a transport defect could not be causing the neurodegeneration.

Finally, Marinkovic analyzed mice overexpressing wild-type human SOD1. When he tracked mitochondria in these animals, their motion was impaired as early as two months of age, much like that of the SOD1-G93A mitochondria. But the SOD1-WT mice did not exhibit the axon dying-back seen in the G93A model; mild axon degeneration was not noticeable until one year of age. Hence, mitochondrial traffic and axon degeneration showed no consistent relationship across the three mouse models.

Misgeld and colleagues thus concluded that the meandering mitochondria and expiring axons were separate events. Manfredi said he had seen similar results in his lab. Even so, the idea that “one event should follow another one in rapid sequence is obviously not the case with neurodegeneration,” he said. Instead, he suggested mitochondrial traffic jams could be one among many “hits” that build up over a lifetime before an animal, certainly a person, succumbs to a disease such as Alzheimer’s, Parkinson’s, or ALS. The G85R mutant is also a rather odd member of the mSOD1 mouse family, he noted, in that it expresses only low levels of an unstable protein and the mice tend to remain healthy for most of their lifespan, only sickening approximately one week before death (Bruijn et al., 1997).

Even though work from Manfredi’s lab has repeatedly correlated mitochondrial transport deficits with ALS (see ARF related news story on Igoudjil et al., 2011), “I am not 100 percent sure that mitochondrial abnormalities are the cause of disease,” he said. Manfredi and Weill Cornell colleague Jordi Magrané are working on stunting the organelle’s traffic in the neurons of animals that are otherwise normal, an experiment they hope will settle the question.

Scott Brady of the University of Illinois in Chicago, who studies axonal transport in neurodegeneration, said the data were solid but the results were limited in scope since mitochondria are only one type of axonal traveler. “A defect in one set of cargo does not necessarily produce a defect in another,” he said. “Mitochondria are not typical in terms of how they move,” Brady added. The Muresans explained that mitochondria spend more time stationary than in motion; when they do travel, it tends to be over short distances, and they frequently reverse direction. Misgeld concurred, noting that other researchers have suggested slowed transport of other cargoes, such as tubulin, could contribute to ALS pathology (Williamson and Cleveland, 1999; Collard et al., 1995). “I think we have a lot more to learn about this link between transport and degeneration,” Misgeld said.—Amber Dance


  1. The mechanisms that lead to synaptic failure, neuronal degeneration, and—finally—neuronal death in most neurodegenerative diseases are still poorly characterized. Abnormal axonal transport has been frequently brought into discussion as a possible cause of the neuronal pathology, especially because the task of transporting organelles, proteins, and mRNAs to their remote sites of function is much more difficult in neurons compared to other cell types, where transport distances are usually short. Certainly, axonal transport appears impeded in many animal models of neurodegenerative diseases, and it is conceivable to assume that the same would also hold true in disease-afflicted human neurons. However, whether the abnormal axonal transport is a cause, a contributing factor, or simply a consequence of the neuronal pathology is still an open question (see, e.g., [1]).

    In their recent paper discussed here, Marinkovic et al. address this question with regard to amyotrophic lateral sclerosis (ALS), using transgenic mouse models of familial ALS (FALS) carrying mutated, human SOD1 genes. By analyzing the transport of fluorescently tagged mitochondria and endocytic vesicles in explanted nerves, the authors set out to determine whether any detected abnormalities in transport precede, or are subsequent to, axon degeneration. Briefly, when performing this analysis in several mouse models of FALS, they find no consistent temporal correlation between the onset of axonal transport deficiencies and the first signs of neuronal degeneration. In some cases, motor neurons with severely compromised transport appear to show normal morphology and function, while in others, transport of mitochondria and endocytic vesicles seems unperturbed in neurons with degenerated axons. Marinkovic et al. conclude that deficits in axonal transport—at least of mitochondria and some endocytic vesicles—and the neuronal degeneration in ALS are independent processes. In other words, ALS-specific neurodegeneration is likely caused by factors other than axonal transport deficiencies. Considering the body of previously published data—strongly suggesting that the transport of mitochondria deteriorates prior to neurodegeneration, and likely causes the synaptic alterations in motor neurons—their results are somewhat surprising.

    The publication of this paper coincides with the publication last month of another paper analyzing transport of mitochondria in the context of a FALS-specific mutation in SOD1 (2). The mutation, G93A, is one of the mutations analyzed by Marinkovic et al. Like Marinkovic et al., Magrané et al. (2) find that transport of mitochondria is reduced in motor neurons. However, unlike Marinkovic et al., Magrané et al. find that the motor neurons expressing mutant SOD1 show severe synaptic alterations. Based mostly on correlative studies, the latter group concludes that "impaired mitochondrial dynamics may contribute to the selective degeneration of motor neurons in SOD1-FALS" (2). There are other, smaller discrepancies between the two studies, for example, the extent by which both anterograde and retrograde axonal transport of mitochondria are affected, or the effect of overexpressing of wild-type SOD1 on axonal transport (Marinkovic et al. find that overexpression of wild-type SOD1 causes significant reduction of mitochondrial transport, while Magrané et al. find no effect). These could be due to the different experimental systems used by the two groups: transgenic mice versus transgenic rats, nerve explants versus neuronal cultures, and—most importantly—adult neurons in situ versus embryonic neurons. Yet, the major discrepancy between the two studies is in the conclusions they reach; this is certainly due to the fact that Marinkovic et al. perform their analysis not only on one, but on several, mouse models of ALS. It would be interesting to see what results Magrané et al. would have obtained in the context of the other SOD1 mutations investigated by Marinkovic et al.

    We think that any conclusion on the role of an abnormal axonal transport on neuronal pathology in ALS—as in any other neurodegenerative disease—should not be drawn solely based on transport of mitochondria or other slowly moving cargo. Mitochondria do not represent the typical cargo for fast axonal transport. They use several molecular motors, and switch quite frequently the direction of movement. Most importantly, mitochondria are stationary most of the time. When they move, they do so by translocating mostly over short distances. Long-distance transport of mitochondria is quite infrequent. If needed in a particular location along the axon, they are brought mostly from vicinal locations. Of course, their importance as providers of energy and relief from oxidative stress makes them particularly important. However, the deficiency in the transport of a cargo that normally is robustly transported over long distances would probably be more detrimental to the health of the neuron than a slightly reduced transport rate of mitochondria.

    On the other hand, even a subtle slowing down of axonal transport could become detrimental, if it triggers a secondary response that itself leads to neurodegeneration. We have recently proposed such a mechanism, where a slowed down axonal transport could trigger a stress response—aimed at correcting axonal transport—that itself leads to the neuronal pathology typical for Alzheimer's disease (3). Certainly, many more studies are needed before one can conclude that a deficient axonal transport causes—or does not cause—the neuronal pathologies characteristic for the various neurodegenerative diseases. One of the difficulties may come from not knowing exactly what is the normal range of axonal transport, and how much variability in transport can be tolerated by neurons.


    . Is abnormal axonal transport a cause, a contributing factor or a consequence of the neuronal pathology in Alzheimer's disease?. Future Neurol. 2009 Nov 1;4(6):761-773. PubMed.

    . Mitochondrial dynamics and bioenergetic dysfunction is associated with synaptic alterations in mutant SOD1 motor neurons. J Neurosci. 2012 Jan 4;32(1):229-42. PubMed.

    . A persistent stress response to impeded axonal transport leads to accumulation of amyloid-β in the endoplasmic reticulum, and is a probable cause of sporadic Alzheimer's disease. Neurodegener Dis. 2012;10(1-4):60-3. PubMed.

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News Citations

  1. San Diego: Mutant SOD1 Bumps Mitochondrial Current Up—Or Down?
  2. Chicago: Axonal Transport Not So Fast in Neurodegenerative Disease
  3. Varicose Axons: Traffic Jams Precede AD Pathology in Mice, Men
  4. Huntington’s Protein Snarls Axonal Traffic
  5. Mitochondria Stumble Their Way Along Axons in ALS Model
  6. Mutant Meddling in Mitochondria Partly Mimics ALS Pathology

Paper Citations

  1. . Role of axonal transport in neurodegenerative diseases. Annu Rev Neurosci. 2008;31:151-73. PubMed.
  2. . Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease. Science. 2005 Feb 25;307(5713):1282-8. PubMed.
  3. . Neuropathogenic forms of huntingtin and androgen receptor inhibit fast axonal transport. Neuron. 2003 Sep 25;40(1):41-52. PubMed.
  4. . Familial amyotrophic lateral sclerosis-linked SOD1 mutants perturb fast axonal transport to reduce axonal mitochondria content. Hum Mol Genet. 2007 Nov 15;16(22):2720-8. Epub 2007 Aug 28 PubMed.
  5. . Mitochondrial dynamics and bioenergetic dysfunction is associated with synaptic alterations in mutant SOD1 motor neurons. J Neurosci. 2012 Jan 4;32(1):229-42. PubMed.
  6. . Imaging axonal transport of mitochondria in vivo. Nat Methods. 2007 Jul;4(7):559-61. PubMed.
  7. . Deficits in axonal transport precede ALS symptoms in vivo. Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20523-8. Epub 2010 Nov 8 PubMed.
  8. . ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron. 1997 Feb;18(2):327-38. PubMed.
  9. . In vivo pathogenic role of mutant SOD1 localized in the mitochondrial intermembrane space. J Neurosci. 2011 Nov 2;31(44):15826-37. PubMed.
  10. . Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nat Neurosci. 1999 Jan;2(1):50-6. PubMed.
  11. . Defective axonal transport in a transgenic mouse model of amyotrophic lateral sclerosis. Nature. 1995 May 4;375(6526):61-4. PubMed.

Further Reading


  1. . Impairments in fast axonal transport and motor neuron deficits in transgenic mice expressing familial Alzheimer's disease-linked mutant presenilin 1. J Neurosci. 2007 Jun 27;27(26):7011-20. PubMed.
  2. . Axonal transport, amyloid precursor protein, kinesin-1, and the processing apparatus: revisited. J Neurosci. 2005 Mar 2;25(9):2386-95. PubMed.
  3. . Fast axonal transport in amyotrophic lateral sclerosis: an intra-axonal organelle traffic analysis. Neurology. 1987 May;37(5):738-48. PubMed.
  4. . Retrograde axonal transport: pathways to cell death?. Trends Neurosci. 2010 Jul;33(7):335-44. PubMed.
  5. . A persistent stress response to impeded axonal transport leads to accumulation of amyloid-β in the endoplasmic reticulum, and is a probable cause of sporadic Alzheimer's disease. Neurodegener Dis. 2012;10(1-4):60-3. PubMed.
  6. . Increased axonal mitochondrial mobility does not slow amyotrophic lateral sclerosis (ALS)-like disease in mutant SOD1 mice. J Biol Chem. 2011 Jul 1;286(26):23432-40. PubMed.

Primary Papers

  1. . Axonal transport deficits and degeneration can evolve independently in mouse models of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2012 Mar 13;109(11):4296-301. PubMed.