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Mecozzi VJ, Berman DE, Simoes S, Vetanovetz C, Awal MR, Patel VM, Schneider RT, Petsko GA, Ringe D, Small SA. Pharmacological chaperones stabilize retromer to limit APP processing. Nat Chem Biol. 2014 Jun;10(6):443-9. Epub 2014 Apr 20 PubMed.
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Scott Small, Dagmar Ringe, Greg Petsko, and their colleagues are to be congratulated on a beautiful piece of science. This paper represents the combination of expert structural biology and AD cell biology to produce simultaneous advances in both arenas. Their results demonstrate rather convincingly that the identified compound (R55) is capable of stabilizing the retromer complex through binding at a Vps35-Vps29 interaction site. The effects of R55 on APP processing also support the notion that enhanced retromer function will tend to shunt APP through a non-amyloidogenic pathway, reduce APP-BACE interaction, and limit Aβ production.
It is worth noting that a small-molecule strategy to stabilize the retromer complex and enhance its function should affect all retromer-mediated traffic. A retromer-based therapeutic strategy for AD will require further refinement to establish target specificity. Nevertheless, this paper provides a nice proof-of-principle that indirect control of APP processing and Aβ production through manipulation of intracellular traffic is a viable approach.
View all comments by James J. LahIcahn School of Medicine at Mount Sinai
My reaction is that the new pro-retromer drug is brilliant and essential, and at the very least, we have a terrific new tool for cell biology at the bench. In contemplating its use in treating or preventing AD, there are some caveats that tend to keep me up at night.
The first is that I have become convinced that the conventional one target-one drug approach is willfully naive. That simple approach made sense before we had the computational tools to begin to address the true complexity of diseases. Genetic predispositions have been present in humans since conception, and many equilibria will shift as a result. Instituting a one target-one drug intervention in adulthood in hopes of a clinical benefit may well turn out to be a quixotic endeavor.
The second caveat is readily addressable in whole animal and human trials. One worries that interfering with such a ubiquitous event as cargo retrieval is likely to have pleiotropic side effects. I am especially worried about the vps10 family since there are other pathogenic molecules therein (e.g., sortilin). That concern notwithstanding, I completely support moving ahead with clinical development.
Looking at this from the perspective of a diabetologist (which I was in a previous life), since retromer-based dysfunction of the insulin receptor may underlie SORCS1-linked type 2 diabetes (T2D), I would love to see a retromer-stabilizing drug tested in Sorcs1 knockout mice and in people with SORCS1 mutations who have T2D.
View all comments by Sam GandyUniversity of Florida
This study raises some intriguing possibilities. Loss of retromer expression has long been noted in AD, with consequent effects on APP processing and Aβ production. However, retromer recycling appears as a nexus for parkinsonism and dementia. Deficits in neuron transmission and early endosome protein sorting and trafficking are highlighted by the recent discoveries of mutations in DNAJC13 and VPS35, most likely mediated by dominant-negative loss of functional WASH complex. That a chemical chaperone can restore functional retromer activity is a remarkable proof of concept. Further R&D might have broad clinical applications in PD-MCI and dementia. These are exciting times.
View all comments by Matthew M J FarrerAarhus University
The paper by Mecozzi et al. elegantly demonstrates how a small drug, R55, is able to stabilize the retromer complex, enabling enhanced neuronal transport of APP (and sorLA) out of early endosomal compartments thereby escaping amyloidogenic processing. These novel data strongly support previous studies from several groups, and adds yet additional evidence that retromer plays a pivotal role in the neuronal trafficking of APP together with sorLA.
The idea to boost retromer activity by selectively stabilizing the interaction between individual components is intriguing, and offers a very beautiful way to rapidly control the level of retromer and the fate of its cargo.
One major challenge to developing this interesting compound into a pharmacologically useful drug will probably be to get R55 into the brain and show that it can exert its function in vivo. So far the report from Scott Small and colleagues only describes how R55 cross-links the subunits VPS29 and VPS35 in neuronal cultures, but they have not yet tested their potential drug in animal models.
It will therefore be highly interesting to see in future studies whether this compound also is able to reduce amyloid production in the brain of mice. Moreover, as retromer is responsible for the retrograde sorting of many cargo receptors besides sorLA (directly) and APP (indirectly), the risk of harmful side effects from using retromer activity as a molecular target against Alzheimer’s disease is high. As the effect described in the present paper is mediated by the triad of retromer, sorLA, and APP, it is also of interest to determine next what other retromer/sorLA-dependent ligand sorting will be affected by R55.
These concerns still need to be addressed before we will find out whether R55 is offering the way for a new pharmacological compound or not. Nevertheless, so far the paper holds great promises, and presents a very elegant approach and innovation towards selectively avoiding amyloid production.
View all comments by Olav AndersenUniversity of Zurich
This is a very carefully done study that combines elegant structural biology, drug discovery, cell biology, and neuroscience. Clearly, endosomal APP is an attractive target and the authors of the study have identified a pharmacological chaperone that stabilizes retromer complex and thus enhances the sorting of APP away from endosomes. This has clear implications for therapy. Of course, one needs to study how other cargoes that depend on retromer are affected and whether there is a way to confer specificity towards APP sorting. But this is the first demonstration that a small molecule could regulate retromer-dependent sorting of APP from the endosomes, and its a very elegant one.
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