Two papers in the 25 September Neuron move axonal transport squarely into the limelight of research on triplet-repeat (or polyQ) diseases, including Huntington’s. One team of scientists, led by Larry Goldstein at the University of California, San Diego, reports that the presence of mutant huntingtin containing an expanded polyQ tract blocked axonal transport in fruit flies. Interestingly, Goldstein et al. also present a physiological function for the normal huntingtin protein with their other finding that axonal transport flows properly only when sufficient levels of it are present. (A physiological role for huntingtin has been stubbornly elusive, as is also true for AβPP/Aβ, α-synuclein, or PrP, for example). The second team, led by Scott Brady, now at University of Illinois, Chicago, found that polyQ proteins block axonal transport directly in axoplasm squeezed from giant squid axons.

Together, the papers raise the question whether axonal transport blockages are a common pathogenic factor underlying many different neurodegenerative diseases. In ALS, mutations in transport proteins are known in patients and in mouse models Puls et al., 2003; also, see ARF related news story and ARF news story). In AD, axonal transport is becoming an active area of investigation (see Alzforum Live Discussion, ARF related news story, and Trojanowski comment below. The field of polyQ disorders has until now focused more on the proteolysis of mutant huntingtin and on the effect of proteolytic fragments on gene expression. Clearly, the nucleus is a place where many things go awry in Huntington’s, write Mel Feany and Albert La Spada in an accompanying preview. But at the same time, neurodegeneration in polyQ diseases correlates better with aggregates in the neuropil than in the nucleus, they add, and full-length huntingtin is known to occur in the cytosol and associated with the cytoskeleton and membrane vesicles.

Shermali Gunawardena and colleagues first tackled the question whether huntingtin has a normal function in axonal transport. When they decreased the expression of neuronal huntingtin with RNAi, they found that cellular organelles accumulated in blockages in embryos of these transgenic flies. Expression of mutant huntingtin essentially did the same. This suggests that too little of the normal protein (i.e., loss of function) and the presence of the mutant protein (i.e., gain of toxic function) create the same phenotype of poisoning normal axonal transport, at least in Drosophila. As for a mechanism, these scientists propose two things. First, mutant polyQ proteins sequester away motor proteins from their vesicle transport function. Second, this problem becomes confounded by the polyQ proteins’ propensity to aggregate and thus physically block passage of bulky cargo organelles through narrow axons.

Györgyi Szebenyi et al. perfused labeled truncated versions of polyQ huntingtin into axoplasm extruded from giant squid. They found that fragments containing the polyQ stretch markedly reduced the speed and capacity of fast axonal transport in both directions. The effect only occurred with huntingtin peptides containing long CAG repeats in the HD-associated range, not with short repeats. These researchers found the same effect when using the androgen receptor protein, which underlies SMBA, a rare polyQ disease, and studied it further in transgenic cell lines.

How do axonal transport abnormalities intertwine with demonstrated nuclear effects of mutant huntingtin fragments? This remains unclear. One possibility is that cytoplasmic polyQ huntingtin causes axonal blockages that lead to progressive synaptic and axonal degeneration, while the fragments in the nucleus cause apoptosis in two parallel pathways of neurotoxicity, Goldstein’s team writes. Another possibility is that axonal transport disruptions somehow activate cell death pathways in mammalian neurons. Future work to reconcile the nuclear toxicity of polyQ proteins with the consequences of transport disturbances in existing animal models for Huntington’s and spinocerebellar ataxias puts within reach a comprehensive model for Huntington’s, Feany and LaSpada write.—Gabrielle Strobel


  1. These two reports from Scott Brady’s and Larry Goldstein’s laboratories are highly significant because they extend the concept that neurodegenerative disease is caused by impaired axonal transport, beyond more common disorders like Alzheimer's, to also include triplet-repeat diseases. The implication is that multiple neurodegenerative diseases may share a similar mechanism. This notion was proposed nearly 20 years ago by Carlton Gajdusek, but many years went by before sufficient technical advances occurred in AD research to provide circumstantial and experimental data supporting this view. Traction in this area began with the demonstration that tau (a microtubule binding protein) was the building block of AD neurofibrillary tangles (NFTs). Also helpful was the resolution of the controversy over the role of NFT formation in AD in 1991 by studies showing that abnormally phosphorylated CNS tau proteins (PHFtau) form the paired helical filaments in AD NFTs, and that excessive phosphorylation of PHFtau reduced its ability to bind microtubules (MTs) and stabilize them in order to support axonal transport. For a detailed review of this research area, see Lee et al., 2001.

    Thus, years before it was discovered that loss of tau function was the consequence of tau gene mutations in hereditary tauopathies, such as frontotemporal dementia with parkinsonism linked to chromosome 17 or FTDP-17, it was already appreciated that wild-type tau, when altered by hyperphosphorylaton in AD, sustained a loss of function that might impair axonal transport and so lead to a neurodegenerative disease. This prompted the hypothesis that the generation of PHFtau depletes neurons of tau able to bind microtubules, thereby leading to brain degeneration in AD. This model predicted that: 1) the conversion of tau into PHFtau disrupts MT-based transport as well as perhaps physically “blocking” transport due to accumulations of PHFs in neurons and their processes, and 2) the failure of neurons to export proteins from the cell body to distal processes and to retrieve substances (e.g., trophic factors) internalized at axon terminals compromises neuronal viability. It was proposed that these events would culminate in neuronal dysfunction and degeneration leading to the onset/progression of AD. Remarkably, nearly all of the predictions of this disease model of tau pathology in AD and related tauopathies were validated in the last four years through studies of tau-transgenic mice. Some of these provided experimental proof that neurodegeneration caused by tau aggregation was linked to axonal transport failure (Isihara et al., 1999). Indeed, a consensus in favor of this notion appears to be building and a whole issue of Neuromolecular Medicine was dedicated to this topic last year.

    It will be important to confirm and extend the findings described in these two studies, which differ in some details. Both papers conclude that impaired axonal transport plays a significant role in mechanisms underlying neurodegeneration. Significantly, the views proposed in these papers complement and extend the earlier concept of a loss of function and impairment of axonal transport when tau is altered in AD, FTDP-17, and other tauopathies. Specifically, the authors of both of these Neuron papers propose that polyQ species acquire a toxic gain of function that disrupts axonal transport. By adding a toxic gain of function in disease proteins to the more well-documented loss of normal function (as in hyperphosphorylated tau), and linking these abnormalities to impaired axonal transport, these two studies open up bold new avenues for advancing insights into mechanisms of neurodegenerative disease. All of this could have substantial implications for the discovery of new and better therapies for AD and other less common neurodegenerative diseases such as Huntington’s, FTDP-17, other tauopathies, and related disorders.


    . Hypothesis: interference with axonal transport of neurofilament as a common pathogenetic mechanism in certain diseases of the central nervous system. N Engl J Med. 1985 Mar 14;312(11):714-9. PubMed.

    . Neurodegenerative tauopathies. Annu Rev Neurosci. 2001;24:1121-59. PubMed.

    . Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron. 1999 Nov;24(3):751-62. PubMed.

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News Citations

  1. Role of the Motor in Motor Neuron Diseases
  2. Dynamitin in Motor Neurons: Dynamite for ALS Research?
  3. Tau Accused of Blocking Transport, Causing APP to Linger and Nerve Processes to Wither
  4. Huntington’s Protein Snarls Axonal Traffic

Paper Citations

  1. . Mutant dynactin in motor neuron disease. Nat Genet. 2003 Apr;33(4):455-6. Epub 2003 Mar 10 PubMed.

External Citations

  1. Alzforum Live Discussion

Further Reading

Primary Papers

  1. . Neuropathogenic forms of huntingtin and androgen receptor inhibit fast axonal transport. Neuron. 2003 Sep 25;40(1):41-52. PubMed.
  2. . Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila. Neuron. 2003 Sep 25;40(1):25-40. PubMed.
  3. . Polyglutamines stop traffic: axonal transport as a common target in neurodegenerative diseases. Neuron. 2003 Sep 25;40(1):1-2. PubMed.