In the July 10 Cell, Frederic Saudou, Sandrine Humbert, and colleagues from the CNRS in Orsay, France, report that huntingtin (htt) enhances transport of brain-derived neurotrophic factor (BDNF) along microtubules. The results offer a plausible explanation as to why striatal neurons, which depend on cortex-derived BDNF for survival, are so specifically and effectively destroyed by Huntington’s disease.

PolyQ expansions in huntingtin are responsible for this lethal neurodegenerative disorder, which slowly kills striatal neurons. Exactly how polyQ-huntingtin wreaks havoc has been debated since the mutation was discovered. Some theories hinge on the fact that the mutant protein forms aggregates. These may be damaging in and of themselves, or they may sequester other essential proteins and thus prevent them from doing their job (see ARF related news story). Other theories have linked polyQ-huntingtin to regulation of BDNF activity (see ARF related news story). More recently, however, it has been suggested that polyQ-huntingtin blocks axonal transport (see ARF related news story). Now, first author Laurent Gauthier and colleagues seem to have linked the last two observations.

Gauthier et al. made the connection thanks to extremely fast 3D videomicroscopy. By labeling BDNF with a variant of green fluorescent protein (eGFP), they were able to measure its movement in vesicles. When Gauthier examined neural cell lines isolated from knock-in mice that expressed either wild-type or polyQ-huntingtin, they found no obvious difference in the localization of BDNF. The speed of BDNF transport, however, was another matter. The number of stationary vesicles was reduced by almost half when wild-type htt was used, mutant htt, however, had no such effect. In addition, the videomicroscopy showed that the vesicles were moving faster in the presence of wild-type htt. To prove that this vesicular fast track was indeed due to huntingtin, Gauthier knocked down its expression with siRNA. This put the brakes on the vesicles, restoring them to their original speed. Web videos documenting this effect are part of the supplemental material on Cell’s journal website.

The slowing, but not stopping, of the vesicles by mutant huntingtin fits with how the disease progresses, as it suggests that neurons succumb gradually, over time. The finding that cells heterozygous for polyQ-htt are as badly affected as homozygous cells indicates a dominant-negative effect, which also fits with Huntington's genetics.

But how exactly does htt affect BDNF transport? To address this question, Gauthier incubated cells with nocodozole, which depolymerizes microtubules. This resulted in a scattering of the BDNF vesicles and inhibition of their movement, suggesting that the factor is transported along microtubules. To find out what other components may keep the BDNF vesicle train on its tracks, Gauthier co-expressed eGFP-htt with huntingtin-associated protein 1, or HAP1. The latter was found to mediate BDNF transport. In fact, htt engineered to lack the HAP 1 binding site failed to stimulated movement of BDNF. HAP1 is well-known for its ability to bridge microtubules to huntingtin (see ARF related news story).

Where does this leave the aggregation hypothesis? In a curious twist, the authors also found evidence that the lethality of polyQ-huntingtin may be due, at least partly, to sequestration of other proteins—the culprits being HAP1, p150glued, dynein intermediate chain (IC), and kinesin heavy chain (HC). When the authors partitioned these components, they found that polyQ-htt has a higher affinity for HAP1 than wild-type htt. Not only that, but they found that this complex pulls in p150glued, and prevents the dynein and kinesin motor proteins from binding to microtubules. These findings appear to have physiological relevance, because by using sucrose gradients Gauthier found that distribution of dynein IC and p150glued is altered in brain samples from Huntington's patients.

As for treatment, the dominant-negative nature of the mutations suggests that inhibiting gene expression might be an approach worth testing. Toward this end, Beverly Davidson and colleagues from the University of Iowa reported in an independent study last week in Nature Medicine that they managed to relieve symptoms of spinocerebellar ataxia, another polyglutamine-expansion disease, in rodents treated with small interfering RNAs directed against the mutated gene. (For more on RNAi therapeutic approaches, see ARF Live Discussion.)—Tom Fagan


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  1. Cortisol, I believe, inhibits BDNF expression or function. Fatty diet (low in Essential Fatty Acids-EFA) causes permanent stress in the offspring—with raised cortisol and homocysteine—when consumed in pregnancy. Fatty adult diet causes mitochondrial uncoupling, impaired ATP formation and superoxide production, by depleting mit. membranes of EFA. There are large unexplained variations in Huntington's onset and severity, which may be explained by the above observations. I have seen HD develop in the 40-year old anxious, fat-eating daughter of a calmer mother, who developed HD at a later stage of life, and progressed more slowly. Nutritionally, the best intervention for HD—until some cure for the genetic fault comes along—would be to institute low-fat, EFA rich diet, and if anxiety is present, add 10 gm daily of Inositol powder supplement, which should lower the cortisol and homocysteine levels, thus improving BDNF function etc.. It wouldn't hurt to throw in some folic acid. Dr Krishna Vaddadi, in far-off Australia, has used EFA with good results. Nobody has yet tried Inositol, which requires the insight to detect chronic anxiety, the best marker for which is probably a history of shyness in childhood.

  2. I find this paper a significant contribution to the field, and one that will undoubtedly engender further work and exploration into potential new therapeutics. This is important for the Alzheimer's field because new approaches designed to increase vesicular transport may significantly aid Alzheimer's victims. Specifically:

    It is interesting to find decreased BDNF transport in Huntington's disease, in view of the decrease in BDNF transcription that was previously reported (Zuccato et al., 2001) and which presumably occurs via polyglutamine-mediated interference with CBP-regulated gene transcription (Nucifora et al., 2001). Importantly, as Gauthier et al. note in their current manuscript, these two mechanisms are not mutually exclusive and could both contribute to neuronal death.

    The parallels that we and others find with decreased BDNF transcription in cortex and hippocampus of Alzheimer's disease (Garzon et al., 2002; Holsinger et al., 2000; Murray et al., 1994; Phillips et al., 1991) suggest BDNF downregulation as a general mechanism for compromising neuronal survival in neurodegenerative diseases.

    Decreases in NGF in nucleus basalis of Alzheimer's disease patients and increases in proNGF in cortex and hippocampus (Scott et al., 1995; Hock et al., 2000; Fahnestock et al., 2001) are also consistent with a defect in cholinergic basal forebrain neuronal transport of neurotrophic factors in Alzheimer's disease.

    ProBDNF is decreased in Alzheimer's disease (Michalski and Fahnestock, 2003), and we are examining retrograde transport of proNGF and proBDNF. The potential involvement of proBDNF should also be examined in Huntington's disease, particularly in light of the demonstrated involvement of the pro domain in activity-dependent secretion of BDNF (Egan et al., 2003).


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  3. The findings of decreased BDNF transport in Huntington's disease, as well as the reports by the Brady and Goldstein groups are significant, as they support the hypothesis that various neurodegenerative disorders display impaired axonal transport defects. These findings parallel the findings from our group showing a deficit in the retrograde transport of NGF within the cholinergic basal forebrain cortical projection system, a reduction in cortical levels of the NGF signal transduction trkA receptor, as well as decreased pre and proBDNF transcription in cortex and hippocampus during the progression of Alzheimer's disease.

    These obsersvation lends support to the emerging concept that several of the most common human neurodegnerative diseases have a common underlying defect in impaired axonal transport in addition to the more traditional pathologic lesions. Transport defects may play pivotal roles in the selective vulnerability of neuronal populations leading to cell death.


    . Increased proNGF levels in subjects with mild cognitive impairment and mild Alzheimer disease. J Neuropathol Exp Neurol. 2004 Jun;63(6):641-9. PubMed.


News Citations

  1. A Potential Mechanism for Cell Toxicity in Huntington's
  2. Huntingtin Regulates BDNF
  3. Huntington’s Protein Snarls Axonal Traffic
  4. Protein-Protein Interactions, Cytoskeleton Implicated in Huntington's

Other Citations

  1. ARF Live Discussion

Further Reading

Primary Papers

  1. . Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell. 2004 Jul 9;118(1):127-38. PubMed.
  2. . RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nat Med. 2004 Aug;10(8):816-20. PubMed.