Li JG, Chiu J, Ramanjulu M, Blass BE, Praticò D. A pharmacological chaperone improves memory by reducing Aβ and tau neuropathology in a mouse model with plaques and tangles. Mol Neurodegener. 2020 Jan 22;15(1):1. PubMed. Correction.
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Columbia University
In 2014, as a joint effort with the Petsko and Ringe labs, we introduced a class of drugs called “retromer pharmacological chaperones” (Mecozzi et al., 2014).
Retromer’s core is a trimer, and one of the most reliable observations from the ever-growing literature on retromer chemical biology is that destabilizing the trimer accelerates its degradation and reduces retromer function. We wondered if the opposite was true. Through a series of steps, we identified two small molecules, R55 and R33, that stabilized the trimer and increased retromer levels. We showed in neuronal culture that the chaperones enhanced retromer’s trafficking function by finding that it increased the flow of APP and the retromer receptor Sorl1 out of the endosome, and reducing amyloid production.
Retromer has been primarily implicated in AD and PD (Small and Petsko, 2015), and studies have been using these pharmacological chaperones in model systems to show that increasing retromer function can ameliorate PD-related pathology (e.g., Follett et al., 2016; Li et al., 2018).
This recent elegant paper by Dominico Particò’s lab adds to the growing number of studies that have used the chaperones to ameliorate AD-related pathology. In a previous study, they showed that APP mutations cause deficiencies in retromer and the retromer-receptor Sorl1, and in cell culture R55 restored retromer and sorl1 levels. In the current study they used R33 (also call TPT-172) in an in vivo mouse study. A previous study by Jessica Young’s lab (Young et al., 2018) used R33 in IPS human neurons, derived from patients with early onset and sporadic AD, to show that retromer can ameliorate amyloid pathology and tau pathology, and that the effect on tau pathology is independent of amyloid. The current study largely agrees with the Young et al. conclusions, showing that R33 can ameliorate amyloid and tau pathology, but since an in vivo mouse study, the main advance is that they show that the chaperone can reduce synaptic pathology and ameliorate cognitive dysfunction. I congratulate them on all the work that went into this long-term study, in which mice were administered R33 for nine months!
More than the trimer, the “retromer” is actually a multimodular protein assembly, with the trimer acting as retromer’s “cargo recognition core.” This recent study, and the others that preceded it, together validate what we had originally considered a remarkable observation: That stabilizing the binding between just two proteins in retromer’s cargo recognition core will enhance the overall function of a complicated, multimodular, trafficking machine.
References:
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.
Small SA, Petsko GA. Retromer in Alzheimer disease, Parkinson disease and other neurological disorders. Nat Rev Neurosci. 2015 Mar;16(3):126-32. Epub 2015 Feb 11 PubMed.
Follett J, Bugarcic A, Yang Z, Ariotti N, Norwood SJ, Collins BM, Parton RG, Teasdale RD. Parkinson Disease-linked Vps35 R524W Mutation Impairs the Endosomal Association of Retromer and Induces α-Synuclein Aggregation. J Biol Chem. 2016 Aug 26;291(35):18283-98. Epub 2016 Jul 6 PubMed.
Lin G, Lee PT, Chen K, Mao D, Tan KL, Zuo Z, Lin WW, Wang L, Bellen HJ. Phospholipase PLA2G6, a Parkinsonism-Associated Gene, Affects Vps26 and Vps35, Retromer Function, and Ceramide Levels, Similar to α-Synuclein Gain. Cell Metab. 2018 Oct 2;28(4):605-618.e6. Epub 2018 Jun 14 PubMed.
Young JE, Fong LK, Frankowski H, Petsko GA, Small SA, Goldstein LS. Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer's Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein. Stem Cell Reports. 2018 Mar 13;10(3):1046-1058. Epub 2018 Mar 1 PubMed.
View all comments by Scott SmallHarvard Medical School and Brigham&Women's Hospital
In our 2014 paper, Scott Small’s lab and ours collaborated to show that R33 (and a related compound, R55, which I think some companies call TPT-260) stabilized retromer in vitro and also increased retromer protein levels in neurons in culture. Treatment with these chaperones successfully lowered Aβ and APP CTF levels in cell culture of neurons from AD transgenic mice, and the reduction was dose-dependent. Many other labs have since used the chaperones in various cell culture studies of AD pathology, tau pathology, and synuclein pathology, and as far as I know, they are good tool compounds and always increase retromer and reduce pathology. A great example of their use is from Jessica Young’s lab (Young et al., 2018), which showed that R33 reduces both Aβ pathology and tau pathology in sporadic and familial AD patient-derived neurons, and the tau pathology reduction was independent of the presence of APP (a very important finding, since up to that point most people had thought tau pathology was always downstream of APP pathology).
Scott, Dagmar Ringe, and I have been very gratified that there have been so many proofs of principle, by so many independent labs, that increase in retromer protein levels can rescue neurons from the pathologies of Alzheimer’s and other neurodegenerative diseases. Since they don’t act directly on plaques or tangles, these treatments also provide evidence that these pathologies may be the smoke, not the fire, in these disorders. Scott and I have written articles that advance the hypothesis that it is endosomal trafficking dysfunction that is the fire. Of course, smoke can still be bad for you, and it may be helpful to clear it, but the best way to deal with a fire is to put out the flames, because if you just get rid of the smoke you can still burn to death.
The principle was certainly established in vitro by our earlier work. This paper nicely extends that proof of principle to animal models. Although the relevance of extreme transgenic models of AD like the one used here to the human disease can (and should) be questioned, the ability of R33 to suppress the pathologies of the disease in vivo, including improving behavioral deficits, is impressive and suggests, as we have argued for many years, that endosomal trafficking in general, and retromer in particular, is a valid therapeutic target.
That said, I’d be surprised if R33 or R55 were useful as human drugs. They are thiophene thioureas and as such are not ideally stable in vivo—R55 is particularly bad in this regard. They can react with nucleophiles to form covalent adducts and their metabolic fates in most organs are unknown. I suspect pharmaceutical chemists would want to find analogs that do not have these issues, and we (and others) have been doing that.
References:
Young JE, Fong LK, Frankowski H, Petsko GA, Small SA, Goldstein LS. Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer's Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein. Stem Cell Reports. 2018 Mar 13;10(3):1046-1058. Epub 2018 Mar 1 PubMed.
View all comments by Gregory PetskoMake a Comment
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