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Watanabe T, Hikichi Y, Willuweit A, Shintani Y, Horiguchi T. FBL2 regulates amyloid precursor protein (APP) metabolism by promoting ubiquitination-dependent APP degradation and inhibition of APP endocytosis. J Neurosci. 2012 Mar 7;32(10):3352-65. PubMed.
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University of Kentucky, Sanders-Brown COA
This is a really interesting and exciting paper. Although we’ve known for some time that the ubiquitin pathway is intimately involved with the development of Alzheimer’s disease at several levels, this is probably the most significant step forward in our understanding of the underlying mechanism in a long while. Although this is an important discovery, there are still some crucial unknowns. For instance, although Watanabe and colleagues do a great deal to advance our knowledge of how FBL2 controls APP processing, we still don’t know very much about its broader role in the degradation of other proteins. In all likelihood, FBL2 probably affects the turnover of multiple targets, and we’re going to need to know more of these to evaluate its real potential as an novel avenue for therapeutic development. Also, their data show that you would likely have to augment the expression or improve the function of FBL2 to tap into this potential, and upregulating something is a harder thing to do than knocking it down or blocking its activity. So targeting this pathway as a therapeutic strategy will be challenging. On the upside, even if it’s a hard pathway to tap into for a therapy, there could be some real potential here for treating other diseases that involve defective protein turnover, in addition to AD. So the payoff could be huge.
Lund University
This paper by Watanabe and colleagues is of considerable interest; it provides evidence that Aβ precursor protein (APP) is ubiquitinated and that FBL2, a component of the SCF E3 ubiquitin ligase complex, is important in regulating APP trafficking, processing, and degradation. A better understanding of the regulated processing and degradation of APP is important, given the focus on Aβ in both diagnostic and therapeutic AD research. (For an excellent recent review on the cell biology of APP, see Rajendran and Annaert, 2012.) Although transmembrane proteins at the plasma membrane are ubiquitinated to induce internalization and degradation in the endosomal-lysosomal system (e.g., the epidermal growth factor receptor), the authors provide evidence that FBL2-induced ubiquitination of APP is more analogous to that of protease-activated receptor-1 PAR1, where ubiquitination inhibits internalization (Wolfe et al., 2007). They show that FBL2 interacts with the C-terminus of APP and, when overexpressed, FBL2 reduces (and when knocked down, increases) both extra- and intracellular Aβ. Their data are strengthened by showing that overexpression of FBL2 reduces Aβ in the brains of transgenic mice.
It is not quite clear how they envision Aβ or APP, which should be associated with endocytic vesicles, to be degraded by the proteasome in the cytoplasm; endosome-associated proteasome might be considered (Almeida et al., 2006). Immunofluorescence microscopy could have been made use of as a complementary method to, for example, confirm the subcellular localization of FBL2, or cell surface dynamics of APP. And using the Aβ/APP antibody 6E10 to detect intraneuronal Aβ in the brain is not optimal, given the controversy about this highlighted by last summer’s ARF Webinar. Overall, the data presented here are quite thorough and provide important new insights into APP metabolism. FBL2 might also provide a new target for experimental therapy.
References:
Rajendran L, Annaert W. Membrane trafficking pathways in Alzheimer's disease. Traffic. 2012 Jun;13(6):759-70. PubMed.
Wolfe BL, Marchese A, Trejo J. Ubiquitination differentially regulates clathrin-dependent internalization of protease-activated receptor-1. J Cell Biol. 2007 Jun 4;177(5):905-16. PubMed.
Almeida CG, Takahashi RH, Gouras GK. Beta-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin-proteasome system. J Neurosci. 2006 Apr 19;26(16):4277-88. PubMed.
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