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. gamma-cleavage-independent functions of presenilin, nicastrin, and Aph-1 regulate cell-junction organization and prevent tau toxicity in vivo. Neuron. 2006 May 4;50(3):359-75. PubMed.

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  1. This is a very interesting paper, which further extends our understanding about PS1-induced toxic gain of function(s). Indeed, increased GSK3 activation (through serine 9 dephosphorylation) has previously been reported in PS1 animal models (Pigino et al.) and cultured neuronal cells (Takashima et al., Irving et al.). However, these studies did not address the role of other γ-secretase proteins such as Nicastrin, and Aph-1, an issue nicely addressed by the studies in Doglio et al. What remains controversial from these and similar studies is the role of tau protein within this mechanism. Although tau is clearly affected as a downstream component in the PS1-GSK3 pathway, it is possible that tau represents one of many more GSK3 targets. This and other studies need to consider the possibility that deregulation of well-characterized GSK3 substrates other than tau (i.e., kinesin-1, CRMP-2, etc.) might be critical components leading to selective neuronal toxicity.

    References:

    . Alzheimer's presenilin 1 mutations impair kinesin-based axonal transport. J Neurosci. 2003 Jun 1;23(11):4499-508. PubMed.

    . Tau phosphorylation in cells transfected with wild-type or an Alzheimer's disease mutant Presenilin 1. Neurosci Lett. 1997 Jan 31;222(2):71-4. PubMed.

    . Presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau. Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9637-41. PubMed.

  2. Note by Alzforum Editor: This paper has been retracted. According to the authors, several of the figures were found to contain serious inaccuracies and no longer support the major conclusions of the paper. Click on retraction page links for complete author statement.

  3. I am saddened and disappointed that irregularities in the figures of this manuscript led to the retraction of this paper. Accordingly, I formally retract my prior commentary discussing this study. We are all reminded to apply the greatest care and integrity to our research.

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