. RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nat Med. 2004 Aug;10(8):816-20. PubMed.

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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 homocysteinewhen 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 HDuntil some cure for the genetic fault comes alongwould 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.

    View all comments by Robert Peers
  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).

    View all comments by Margaret Fahnestock
  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.

    View all comments by Elliott Mufson

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