Ishikura N, Clever JL, Bouzamondo-Bernstein E, Samayoa E, Prusiner SB, Huang EJ, Dearmond SJ.
Notch-1 activation and dendritic atrophy in prion disease.
Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):886-91.
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Notch signaling is a highly conserved pathway that plays essential roles in cell proliferation and differentiation. It is unclear, however, whether Notch-1 signaling does participate in cellular events leading to neurodegeneration. In this, S. J. DeArmond and collaborators report an unappreciated contribution of Notch-1 signaling in neurodegenerative diseases, and specifically in prion disease. Previous studies showed that contact-dependent inhibition of neurite growth in cortical neurons is mediated by Notch-1/2 signaling (Sestan et al., 1999). Notch-1-dependent inhibition of dendritic growth seems to involve signaling of the Notch intracellular domain (NICD) to the nucleus (Redmond et al., 2000).
In the present study, the authors convincingly demonstrate that Notch-1 mRNA and the Notch intracellular domain (NICD) are upregulated in the neocortex of mice infected with a disease-causing isoform of the prion protein (PrPSc). In prion-infected mice, NICD accumulation in the nucleus and synaptosomes is associated with reduced dendritic length of cortical neurons. In vitro studies also demonstrated shorter dendritic processes in differentiated scrapie-infected neuroblastoma (ScN2a) cells. This phenotype was specifically reversed after lowering Notch-1 expression with siRNAs.
Although the cellular mechanisms that regulate Notch-1 expression by PrPSc are unclear, these findings suggest that altered Notch-1 signaling may be responsible for dendritic atrophy in this model of prion disease. Moreover, the current data strongly support the previous findings demonstrating Notch-dependent inhibition of neurite growth in the developing brain. Interestingly, increased Notch-1 expression has also been found in hippocampal neurons of sporadic Alzheimer disease (Berezovska et al., 1998), a disorder also characterized by profound dendritic degeneration. It may not seem too unreasonable to imagine a common molecular mechanism underlying dendritic atrophy in different neurodegenerative diseases.
This article shows that the Notch intracellular domain (NICD), the proteolytic fragment that mediates signaling from the Notch receptor, is increased in prion-infected CD1 mice, and this increase correlates with dendritic atrophy. Moreover, cultured neurons from these mice were transfected with siRNA toward Notch-1, and the subsequent knockdown of Notch-1 apparently rescued neurite growth to normal in this cell culture system. The authors suggest that γ-secretase inhibitors might have similar effects by preventing the formation of NICD, but it is unclear why this experiment was not performed: With the neuronal culture system established, any number of commercially available cell-permeable inhibitors of γ-secretase could have been tested to see if the effects were similar to that observed with siRNA treatment.
Although not explicitly mentioned by the authors, it may be tempting to speculate that lowering amyloid-β production via γ-secretase inhibition for AD may have the added benefit of preventing dendritic atrophy by blocking Notch signaling. However, in contrast to what is seen in these prion-infected mice, there is little or no evidence for increased NICD production in AD. Indeed, most AD-causing mutations in presenilin (the catalytic component of γ-secretase) apparently have a decreased ability to generate NICD (1). Moreover, conditional knockout of presenilin in the postnatal mouse brain interferes with synaptic plasticity (2). In any event, treatment with γ-secretase inhibitors results in clear Notch-based toxic effects on the immune system and the gastrointestinal tract (3,4); thus, it now seems clear that the ideal γ-secretase inhibitor for AD therapy should lower amyloid without affecting Notch.
1. Song W, Nadeau P, Yuan M, Yang X, Shen J, Yankner BA. Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations. Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):6959-63. Abstract
2. Saura CA, Choi SY, Beglopoulos V, Malkani S, Zhang D, Shankaranarayana Rao BS, Chattarji S, Kelleher RJ, Kandel ER, Duff K, Kirkwood A, Shen J. Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron. 2004 Apr 8;42(1):23-36. Abstract
3. Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, Engstrom L, Pinzon-Ortiz MC, Fine JS, Lee HJ, Zhang L, Higgins GA, Parker EM. Chronic treatment with the gamma -secretase inhibitor LY-411,575 inhibits Abeta production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem. 2004 Jan 6. Abstract
4. Searfoss GH, Jordan WH, Calligaro DO, Galbreath EJ, Schirtzinger LM, Berridge BR, Gao H, Higgins MA, May PC, Ryan TP. Adipsin: a biomarker of gastrointestinal toxicity mediated by a functional gamma secretase inhibitor. J Biol Chem. 2003 Aug 29. Abstract
This paper describes a correlation between prion infection and increase in NICD. To establish a causative role for Notch in the pathology, the authors reproduce the observations establishing that Notch can control neurite outgrowth in cell lines. These two loosely connected observations lead to the dangerous suggestion that inhibition of Notch-1 cleavage with γ-secretase inhibitors might reduce NICD levels and slow dendritic atrophy in CJD cases. However, the authors ignore published reports establishing that inhibition of γ-secretase in mice can result in death due to synaptic dysfunction (Saura et al., 2003). Reduction in Notch dose can cause learning and memory deficits (Costa et al., 2003), and complete loss of Notch alone is lethal in adult animals (Presente et al., 2001; Presente et al., 2004). In my humble opinion, combining the two insults (γ-secretase inhibition and prion accumulation) will hasten, not reduce, the demise of cortical neurons.