. Transneuronal propagation of mutant huntingtin contributes to non-cell autonomous pathology in neurons. Nat Neurosci. 2014 Aug;17(8):1064-72. Epub 2014 Jul 13 PubMed.


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  1. This is a very elegant study that did some nice work to show that mHtt aggregates can move between neurons in brain and organotypic slice cultures of R6/2 mice. The study finishes with the use of toxins that block vesicle fusion at the synapse to suggest that synaptic activity might be mediating transneuronal movement somehow by mHtt aggregate release at the synapse. An alternative interpretation is that these toxins, by blocking synaptic activity, are disrupting the formation of synapses. This, in turn, could prevent two neurons from forming a close association, and thus might indirectly reduce transneuronal movement of aggregates that is in fact independent of neuronal firing. Given their experimental system, it is difficult to tease apart these two problems (vesicle fusion/release of mHtt vs. synapse formation with juxtaposition of cell membranes). However, in other systems it would be possible to test directly whether firing of an existing synapse would promote transcellular movement of aggregates.

    Additionally, the authors infer that human neurons transplanted into a “toxic” environment of R6/2 brain have loss of function/anatomic structure due to transfer of mHtt proteins (Fig 1). This could be more directly tested. For example, application of antibodies against mHtt to the culture could be tested to block the induction of these abnormalities. Additionally, knockdown of wt Htt in the human neurons could be tested to determine whether a “prion-like” mechanism is required for the mHtt to have its effect in the co-culture.

    All in all, this is a provocative study, and it raises important questions to be tested in further work.

    View all comments by Marc Diamond
  2. This is an elegant series of experiments using interesting and informative models. The findings complement a growing literature demonstrating the cell-to-cell spread of pathogenic protein seeds formed by Aβ, PrP, tau, alpha-synuclein, SOD1 and others. Given the alacrity with which neurons take up, transport, and disseminate all sorts of cargo, including viruses and foreign proteins, it seems more and more that it would be surprising to find a neurologic proteopathy that doesn't involve these mechanisms.

    View all comments by Lary Walker

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  1. Huntington’s Protein Charged with Trans-synaptic Spread of Pathology