. Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice. Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3528-33. PubMed.


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  1. The paper by Di Pardo et al. shows a remarkable improvement of motor impairment by intraventricular ganglioside GM1 treatment. It is particularly exciting, since this treatment seems to improve the phenotype even after neurological symptoms have presented.

    Altered GM1 levels have been linked to other neurodegenerative disorders such as Parkinson’s disease (PD), and GM1 treatment in a primate PD model seems to almost completely restore motor deficits after treatment with the toxin MPTP, which induces parkinsonism in mice (Schneider et al., 1992). While the protective mechanism in PD models is also not clear, a more recent study suggested that GM1 reverses lysosomal dysfunction induced by synuclein aggregation (Wei et al., 2009). Interestingly, GM1 can also directly inhibit in vitro formation of α-synuclein amyloid while promoting the formation of putatively non-toxic, off-pathway oligomers (Martinez et al., 2007). This direct effect on the aggregation state of the protein may provide a mechanistic explanation for the protective effect of GM1 in PD. It would be interesting to assess whether GM1 can also directly affect the aggregation rate of mutant huntingtin protein.

    While the link to huntingtin phosphorylation is interesting, I look forward to follow-up studies that will provide more detail on the rescue mechanism of GM1. Since GM1 is involved in many cell signaling activities, including neuronal development and synaptic activity, it is possible that GM1 works through general neurotrophic actions by promoting axonal sprouting or branching as previously demonstrated (Roisen et al., 1981). This may explain the apparent protective effects of GM1 in other chronic neurodegenerative diseases as well as acute neuronal injuries that result from ischemia. In this paper by Di Pardo et al., a pathological analysis of the striatum would be instructive, and may provide additional clues into the mechanism of GM1 treatment. For example, it would be interesting to see whether GM1 promotes neurite outgrowth or restores cell volume of medium spiny neurons.

    Overall, the work is very exciting and may provide a new therapeutic avenue for the treatment of HD. It will be interesting to determine whether GM1 itself, or small molecules that can mimic the action of GM1, will be effective when administered systemically such as through gastrointestinal or intravenous routes.


    . Recovery from experimental parkinsonism in primates with GM1 ganglioside treatment. Science. 1992 May 8;256(5058):843-6. PubMed.

    . Protective role of endogenous gangliosides for lysosomal pathology in a cellular model of synucleinopathies. Am J Pathol. 2009 May;174(5):1891-909. PubMed.

    . GM1 specifically interacts with alpha-synuclein and inhibits fibrillation. Biochemistry. 2007 Feb 20;46(7):1868-77. PubMed.

    . Ganglioside stimulation of axonal sprouting in vitro. Science. 1981 Oct 30;214(4520):577-8. PubMed.

  2. This is an interesting paper, as it is the first to show that in-vivo administration of ganglioside increases mutant huntingtin (mHtt) phosphorylation and improves motor phenotype. Significantly, ganglioside is a natural cell membrane component with rare side effects, which might prove advantageous for future therapeutic development. This paper also demonstrates for the first time that an agent targeting mHtt phosphorylation is beneficial in a model of Huntington's disease. There are some caveats.

    1. The administration of GM in this paper is directly through cerebral ventricles, and it is unknown if the effects of peripheral administration are beneficial.

    2. The effect of long-term use and longitudinal effects after administration should be followed; for example, does body weight change after the GM administration? As YAC128 mice are obese, the rotarod test results are partially dependent on body weight.

    3. Other direct neuroprotective measures should be followed up in order to develop GM1 as a therapeutic.

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  1. Huntington’s Strategies Tap Transcription, Htt Phosphorylation