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HYPOTHESIS Please cite this article as: Richard N. Re, Does intracrine amplification provide a unifying principle for the progression of common neurodegenerative disorders? Hypothesis 2015, 13(1): e2, doi:10.5779/hypothesis.v13i1.413 1/5 Scientific Director, Ochsner Clinic Foundation New Orleans, Lousiana, United States Received: 2014/09/04; Accepted: 2014/10/06; Posted online: 2015/05/26 *Correspondence: [email protected] © 2015 Richard N. Re. This is an Open Access article distributed by Hypothesis under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. kind of action is strong and the intracrine primitive intracrine mechanism: proteins traffic from cell to cell, cause disease, and Does intracrine amplification provide a unifying principle for the progression of common neurodegenerative disorders? Richard N. Re* associated with these pathogenic proteins subsequent induction of misfolding and and that principles of intracrine biology— pathology in those cells. This likely occurs homeodomain and in particular the intracellular amplifica- in Alzheimer's disease (AD), Parkinson's provide a clear example. Intracrines can, then re-capitulate themselves to affect proteins, such as hormones and growth factors, can act within their cells of synthesis or after secretion and internalization by target cells. These factors are called intracrines; aspects of their biology have been defined. The actions of these factors are mirrored in the cell-to-cell transmission of prions and prion-like proteins in common neurodegenerative disorders such as Alzheimer's disease. This suggests the possibility that intracrine-like functionality is Illustration by Eloïse Kremer factors tion of intracrines—can point to therapeutic disease (PD), amyotrophic lateral sclerosis as in angiogenesis, interact in the intra- other cells. Mechanisms of cell trafficking strategies for the treatment of these diseas- (ALS), tauopathies, chronic traumatic cellular space to form intracellular regula- employed by intracrines have been es. Here, possible modes of amplification encephalopathy (CTE), and other NDDs. tory networks. Intracrines traffic between of prion-like particles in neurodegenerative These diseases result from the trafficking ABSTRACT Many extracellular signaling transcription cells following secretion and uptake by proposed to be the operative modes of trafficking for misfolded peptides as well. disorders are explored. of disordered proteins, and, in their inher- target cells, but also via trafficking in Exosomes are released at synapses and INTRODUCTION The pathogenesis of ited forms, also from the cell-autonomous exosomes and possibly trafficking via exosomal trafficking of misfolded pro- production of mutant proteins susceptible nanotubes2,3,4. teins complements, or even substitutes transmissible spongiform encephalopathies (TSEs) such as Creutzfeldt-Jakob to misfolding . 1 There are parallels between the actions disease, kuru, scrapie, and bovine spongi- In recent years, considerable evidence of intracrines and proteins involved in form encephalopathy (mad cow disease) has been developed to show that many neurodegenerative disease; both involve was defined by Prusiner who demon- extracellular signaling proteins can act protein trafficking between cells and the strated that misfolded prion proteins could within their cells of synthesis or in target establishment of an altered state in tar- traffic between cells and induce mis- cells after secretion and internalization by get cells with subsequent propagation. folding in normal prion proteins in target target cells. These factors are called intra- In the case of physiological intracrine cells. As he predicted, other misfolded crines; aspects of their biology have been protein defined neurodegenerative disorders 2,3,4 action, this process generally results in . Many intracrines generate in- altered hormonal responsiveness or dif- (NDDs)—which, unlike TSEs, are not tracellular feed-forward loops that result naturally in target cells being placed in altered (dif- neuropeptides, it results in toxicity. These infectious—involve trafficking of abnormal proteins between cells with ferentiated) states. The evidence for this ferentiation. In the case of the misfolded neurodegenative disorders display a HYPOTHESIS for, the secretion of misfolded peptides and/or their release from extracellular plaques or dying cells. The trafficking of misfolded proteins in nanotubes has been suggested. So there are commonalities between intracrine action and the actions of misfolded neural proteins. A frequent feature of intracrine networks which potentially informs the understanding of TSEs, and therefore potentially of other NDDs, is the notion that intracrine systems often are self-sustaining through Vol.13, No.1 | 2015 | hypothesisjournal.com HYPOTHESIS Protein amplification in neurodegenerative disorders 2/5 Re the mechanism of feed-forward regulato- internalization by target cells, up-regula- as a paradigm for intracrine-like action Copper up-regulates PrPc synthesis6. produced by abeta protein requires the ry loops. This implies an active amplifica- tionofintracrineproteinintargetcells,action in neurodegeneration because they are PrPc is found in the nucleus and could presence of both PrPc and the micro- tion step, which, if present in NDD, could within target cells) are observed in the transmissible not only between cells but serve to buffer copper there. Were a tubule-associated protein tau (which provide a therapeutic target. Similarities actions of prion-like proteins in the neu- between organisms. That is, they are in- significant amount of the normal prion forms intracellular tangles that correlate between normal and abnormal intra- rodegenerative mentioned fectious (e.g., mad cow disease). Here, protein to be replaced by scrapie prion, with disease severity in AD) 5,6,7. Copper crine and prion biology, including the above. The differences are that in the the hypothesis is applied more widely copper buffering would be reduced and up-regulates the synthesis of both PrPc potential physiologic intracrine function- neurodegenerative diseases, the pri- to the other common neurodegenerative PrP synthesis increased. Because it and APP suggesting that disordered ing of normal forms of NDD-associated mary trafficking protein is a misfolded disorders, which have not been shown appears that newly synthesized PrPc is copper handling could lead to amplifi- proteins, have been reviewed else- form of a normal cellular protein rather to be infectious, and the implication of the preferred substrate for conversion cation of APP synthesis and secondarily where5. From this, comes the general than a normal intracrine, and rather than the hypothesis that amplification is char- to PrPsc by the abnormal scrapie prion, to increased abeta protein synthesis5. notion that some normal homologues of producing a physiologic effect in target acteristic of these disorders is similarly this would increase the cellular load of Abeta1-40 can in turn up-regulate tau7. pathological prions at times act as intra- cells, the misfolded protein produces a widely applied to neurodegenerative abnormal prion disorders c 1,5,6 . Toxicity, and traffick- The requirement for PrPc in abeta protein crines and employ feed-forward loops pathological effect. Nonetheless, the ba- disorders. Moreover, possible mechan- ing of PrP (amplification). Once prion transforma- sics of the processes are similar and this isms of amplification of the relevant pro- cells, tion occurs, this intracrine functionality is suggests that focusing on common in- teins in these disorders are proposed. To increased synthesis of PrPc in scrapie mode of copper influx and trafficking in coopted, or aberrant intracrine function- tracrine functionality could lead to a new do this, the nature of TSEs is briefly re- infected neurons (as opposed to Peyer’s neurons, in addition to any role played ality is developed, to spread pathology in understanding of not only the nature of viewed and the illustrated principles then patch been by direct PrPc binding of abeta protein. the nervous system. TSEs but also of other common neuro- applied more widely. Potential intracrine detected, no detailed exploration of this APP and abeta protein bind copper, and HYPOTHESIS It is proposed that the degenerative disorders. In particular, the pathways in selected neurodegenerative issue has been undertaken and inter- their arrival via exosomes in target cells hypothesis that these neuroencepha- disorders are proposed. pretation of the available data is compli- could disrupt copper regulation in those lopathies are intracrine in nature implies SUPPORTING INFORMATION It is pro- cated by neuronal cell loss during cells, enhancing disease propagation. posed that the up-regulation, by any of In amyotrophic lateral sclerosis, two mis- neurodegenerative diseases recently suggested to develop from the propagation of transmissible proteins between brain cells—diseases such as Creutzfeldt-Jakob disease and other transmissible spongiform encephalopathies, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (Lou Gehrig disease), and chronic traumatic encephalopathy—result from distorted intracrine physiology. That is, the same actions characteristic of intracrines (function within the cell, trafficking by one means or another to adjacent cells, that transmissible prion-like protein upregulation (amplification) occurs in target cells. If the amplification of intracrines in target cells is mirrored in the amplification of prion-like proteins in target cells as is hypothesized here, this would present a new therapeutic target. The notion that intracrine biology plays a role in these common neurodegenerative disorders has been suggested elsewhere in the case of the transmissible spongiform encephalopathies (TSEs) 5. The TSEs serve a variety of mechanisms, of the normal forms of the common NDD-associated proteins is essential for disease progression. In the case of the TSEs, one can note that synthesis of normal cellular prion protein PrPc is essential to the prop- sc via endosomes to nearby could then lymphocytes) result. has Although not disease5. Also, it is possible that upregulation of PrPc synthesis need only be required in the initial phase of infection so as to produce sufficient abnormal prion protein to permit ongoing production with a more normal rate of PrPc production. in vitro neurotoxicity could result from the protein's role in providing an efficient folded proteins have been associated with disease: copper-zinc superoxide dismutase 1 (SOD1) and TDP431,10-13. For brevity, TDP43 will be discussed here. TDP43 is a multifunctional DNA and RNA binding protein that is involved in agation of abnormal scrapie prion PrPsc 1-9. Similarly, the progression of AD requires RNA splicing. Interestingly, it controls Suppression of PrPc synthesis at any the production of amyloid precursor its own synthesis by binding its own point stops disease progression . PrP , protein (APP), which is cleaved to form mRNA. Decreased TDP43 protein leads but not PrPsc, binds and transports cop- the toxic extracellular plaque-forming to increased translation of its message per (as well as iron and zinc) into cells. abeta protein, while in vitro neurotoxicity and increased synthesis of the protein; HYPOTHESIS Vol.13, No.1 | 2015 | hypothesisjournal.com 8 c HYPOTHESIS Protein amplification in neurodegenerative disorders 3/5 Re that is, it leads to up-regulation. In ALS, copper, zinc, and iron are transported common up-regulation of PrPc, and other substrate proteins. Up-regulation For example, reducing CNS copper con- TDP43 aggregates in the cytoplasm with APP by copper, STOX1A may represent of substrate proteins could then lead to centrations by dietary or other means a near absence of TDP43 in the nucleus. participation of PrPc in the disease5,6,9. another case of interaction between the the stochastic development of misfolded would be expected to decrease PrPc syn- into cells by PrPc, these data suggest Toxicity likely results from the loss of However, whereas PrP down-regulation pathologies of the NDDs. Although tau proteins which, in turn, serve as seeds for thesis and disease progression in TSEs TDP43-mediated regulation of cellular by zinc (secondary to internalization of tangles are not seen in ALS, they are the formation of aggregates and disease and possibly in other NDDs. Although an propagation18,19,20. abeta protein preparation recently has c mRNAs as a result of TDP43 sequestra- PrPc by zinc) may be beneficial in TSEs, prominent in the related disorder chronic tion in cytoplasmic aggregates. Thus, if as noted in the case of TDP43 aggre- traumatic encephalopathy (CTE) where an abnormal TDP43 fragment is taken gation, the effects of zinc appear to be abeta protein, TDP43, and alpha- up by a target cell and seeds cyto- more complex in other NDDs. synuclein inclusions can also be found plasmic aggregation of endogenous in some cases17. Trauma likely produces TDP43, then cellular TDP43 will be upregulated and the disease will progress. It is possible that another form of amplification occurs in ALS. APP and cellular copper are increased in ALS. There is some indirect evidence to suggest modest TDP43 up-regulation by copper compounds13. Tissue iron also is increased suggesting impaired APP ferroxidase activity as may occur in AD secondary to extracellular zinc release from plaques12. If the increased cellular iron in ALS does in fact result from increased extracellular zinc (whether through ferroxidase inhibition or some other effect on APP iron export), this could be important. Extracellular zinc causes intracellular TDP43 aggregation, thereby TDP43 down-regulating and up-regulating functional TDP43 synthesis . This would be expected to 11 enhance production of TD43 prion-like particles and disease spread. Because Several NDDs, while expressing one prominent misfolded protein, express variable levels of others, suggesting some commonality of regulation and/or intracrine-like regulatory networking. One protein commonly involved is tau, which also appears to be the primary protein in disorders such as progressive supranuclear palsy. Possible amplification mechanisms for tau, in addition to upregulation by abeta1-40, are only beginning to emerge. The transcription factor STOX1A in some circumstances can upregulate tau. STOX1A down-regulates CNTNAP2, a member of the neurexin family. In the hippocampus of AD patients, STOX1A expression is upregulated, while CNTNAP2 is downregulated 14,15,16 STOX1A, a . Thus, in the case of mechanism which a wide-ranging disorder, possibly because cytoplasmic RNA/protein stress granules are formed after trauma to protect the brain, and these lead to the aggregation of the mRNAs of many disease-related proteins. Alterations in the amounts of these proteins could lead to disordered homeostasis, including disordered transitional metal homeostasis. Amplification of each factor could then occur. For example, TDP43 RNA is sequestered in stress granules and this should up-regulate TDP43 gene expression. Up-regulated TDP43 interacts with tau mRNA and, depending on the details of this interaction and the rate at which TDP43 is aggregated, the result could be up-regulated tau mRNA translation. up- Similarly, the mRNA binding protein The hypothesis has several implications. First, evidence of substrate protein amplification should be sought in all NDDs— and confirmed in Parkinson's disease where amplification has already been reported21. Second, prevention of amplification is a disease-controlling strategy; complete knock-down of substrate protein is unnecessary. Third, intracrinelike networks linking the regulation of various misfolded proteins should be sought; their interruption would be therapeutically beneficial in disease modification. These networks, usually weak and indolent, can, as is likely in some cases of CTE and AD, be more robust. They are likely mediated by misfolded proteindriven regulation of transition metal transport. Fourth, PrPc likely plays an important role in the non-heritable forms of many of these disorders, not only in TSEs, by virtue of its ability to transport copper, zinc, and iron with secondary regulation of substrate proteins (this need been reported to cause disease somewhat resembling AD pathology in PrPc-/- knockout animals (while a five-fold over-expression of PrPc in transgenic animals was actually protective), and although PrPc levels have been reported to be reduced in sporadic (but not heritable) AD frontal cortex, PrPc expression is required for neurotoxicity in vitro and in at least one in vivo model suggesting a complex relationship between PrPc and AD5,22-24. Indeed, there is evidence that at least some of the likely pathological interaction between PrPc and abeta protein involves the direct binding of the two. But PrPc accounts for only about 50% of the cell binding of abeta protein and so it is likely that other cell proteins can at least partially substitute for it 22. Additional research will be required to define the role of PrPc in AD, but it must be noted that abeta protein is the major prionlike protein involved in AD, and PrPc likely plays only a permissive or supplemental role5,22. regulates tau may directly participate HuD is sequestered in stress granules in neurodegeneration in AD through and this relieves the protein's suppres- not be the case in genetic forms of the Nonetheless, it is likely that PrPc knock- the down-regulation of CNTNAP2. Like sion of tau synthesis. Intracrine-like reg- disorders where amplification can be down in AD is beneficial. In ALS, PrPc tau, up-regulation by abeta1-40 and the ulatory networking could up-regulate likely facilitates pathogenic zinc entry unnecessary). HYPOTHESIS Vol.13, No.1 | 2015 | hypothesisjournal.com HYPOTHESIS Protein amplification in neurodegenerative disorders 4/5 Re into cells and PrPc is therefore a possi- phenotype changes and knocking down the neurodegenerative disorders differ Foundation, and is on the faculty of Tulane prion infection prevents disease and reverses spon- ble therapeutic target in that disorder as PrPc in PrPsc infected mice produces from those involved in the normal physi- University School of Medicine. giosis. Science.2003;302:871-4. REFERENCES 9 Watt NT, Taylor DR, Kerrigan TL, Griffiths HH, well as in TSEs . Several drugs such as definite therapeutic benefit . The thrust ologic up-regulation of the respective glimepiride, all-trans-retinoic acid, aste- of all these observations is the sugges- proteins. Therefore, these neurodegen- mizole, and tacrolimis have been shown tion that because of interactions be- erative disorders properly should be con- to lower cell surface PrPc expression at tween prion-like proteins, it is possible sidered intracrine-like to distinguish them 5,11 8,25 one concentration or another; they could c that certain interventions such as PrP from physiological intracrine systems. serve as prototypes for the development knock-down or metal chelation could They utilize an aberrant intracrine physi- of common therapies for NDDs and in prove beneficial in more than one dis- ology. This has a variety of implications particular for TSEs, ALS, and CTE 25-27. ease. That is, just as physiological intra- including potential therapeutic implica- Glimepiride, approved for the treatment crines can form interacting networks, so tions. Currently, a great deal of effort is of diabetes mellitus, may be a particularly too may pathological prion-like proteins. directed to devising methods for limiting useful prototype not only in TSEs where If so, this would present therapeutic op- the spread of prion-like proteins between it lowers cell surface PrPc, but also in portunities. Finally, in addition to their cells. The hypothesis presented here AD, both because it lowers cell surface established roles in the aggregation of suggests, among other things, that PrPc (and therefore disease-enhancing misfolded proteins, it is argued here that aberrant protein amplification should PrPc pathologic effects) and because it transition metals play important roles in be considered a therapeutic target in all induces shedding of PrPc into the extra- protein amplification. Interrupting that of these disorders. More importantly, al- cellular space where it can bind abeta amplification likely also is a common though TSEs serve as the paradigm for protein—a mechanism that has been therapeutic strategy in these neurode- intracrine involvement in neurodegen- proposed to be protective in the PrPc generative disorders. erative disorders, it is proposed here CONCLUSION It is hypothesized here that common intracrine mechanisms are over-expression transgenic model mentioned above 22,23,26 . that there are clear parallels between operative in all these neurodegenerative diseases.H 1 Prusiner SB. A unifying role for prions in neurodegenerative diseases. Science. 2012;336:1511-3. http://dx.doi.org/10.1126/science.1222951 2 Re RN, Cook JL. Senescence, apoptosis, and stem cell biology: the rationale for an expanded view of intracrine action. Am J Physiol Heart Circ Physiol 2009; 297:H893-901. Epub 2009 Jul 10. http://dx.doi.org/10.1152/ajpheart.00414.2009 3 Re RN, Cook JL. The physiological basis of intracrine stem cell regulation. Am J Physiol Heart Circ Physiol. 2008;295:H447-53. http://dx.doi.org/10.1152/ajpheart.00461.2008 4 Re RN, Cook JL. An intracrine view of angiogenesis. Bioessays 2006;28:943-53. 5 Re RN. Could intracrine biology play a role in the pathogenesis of transmissable spongiform encephalopathies, Alzheimer's disease and other neurodegenerative diseases? Am J Med Sci. 2014;347:31220. http://dx.doi.org/10.1097/MAJ.0b013e3182a28af3 6 Armendariz AD, Gonzalez M, Loguinov AV, Vulpe Zinc, because it internalizes with PrP physiologic intracrine action and the without up-regulating PrP synthesis, pathological action of prion-like proteins. ACKNOWLEDGEMENT This work was could act beneficially in TSEs (but likely At the same time, there are clear differ- funded by the Ochsner Clinic Foundation. not in other NDDs) by internalizing cell- ences between normal intracrine func- surface PrP . Intrathecal administration tion and the action of prion-like proteins CONFLICTS OF INTEREST Author de- 7 Wang C, Wurtman RJ, Lee RK. Amyloid precur- of liposomes containing PrP antisense in neurodegenerative diseases. For ex- or anti-PrPc siRNA also could be con- ample, intracrine action is generally sidered. PrPc knock-down is not likely to physiological, whereas misfolded prion- be harmful given the fact that transgenic like proteins are pathological; also the PrP mechanisms of protein amplification in c c c 5,9 c c-/- animals demonstrate minimal CD. Gene expression profiling in chronic copper overload reveals upregulation of Prnp and App. Physiol Genomics. 2004;20:45-54. clare no conflicts of interest. sor protein and membrane phospholipids in primary ABOUT THE AUTHOR The author is a physi- cortical neurons increase with development, or af- cian who conducts research on the cellular biology of vasoactive proteins. He currently serves as Scientific Director, Ochsner Clinic ter exposure to nerve growth factor or Abeta(1-40). Brain Res. 2000;865:157-67. 8 Mallucci G, Dickinson A, Linehan J, Klöhn PC, Brandner S, Collinge J. Depleting neuronal PrP in HYPOTHESIS Rushworth JV, Whitehouse IJ, Hooper NM. Prion protein facilitates uptake of zinc into neuronal cells. Nat Commun. 2012;3:1134. http://dx.doi.org/10.1038/ncomms2135 10 Da Cruz S, Cleveland DW. Understanding the role of TDP-43 and FUS/TLS in ALS and beyond. Curr Opin Neurobiol. 2011;21:904-19. http://dx.doi.org/10.1016/j.conb.2011.05.029. 11 Caragounis A, Price KA, Soon CP, Filiz G, Masters CL, Li QX, et al. Zinc induces depletion and aggregation of endogenous TDP-43. Free Radic Biol Med. 2010;48:1152-61. http://dx.doi.org/10.1016/j.freeradbiomed.2010.01.035 12 Duce JA, Tsatsanis A, Cater MA, James SA, Robb E, Wikhe K, et al. Iron-export ferroxidase activity of b-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell. 2010;142:857-67. http://dx.doi.org/10.1016/j.cell.2010.08.014 13 Parker SJ, Meyerowitz J, James JL, Liddell JR, Nonaka T, Hasegawa M, et al. Inhibition of TDP-43 accumulation by bis(thiosemicarbazonato)-copper complexes. PLoS One. 2012;7:e42277. http://dx.doi.org/10.1371/journal.pone.0042277 14 van Abel D, Hölzel DR, Jain S, Lun FM, Zheng YW, Chen EZ, et al. SFRS7-mediated splicing of tau exon 10 is directly regulated by STOX1A in glial cells. PLoS One. 2011;6:e21994. http://dx.doi.org/10.1371/journal.pone.0021994 15 van Dijk M, van Bezu J, Poutsma A, Veerhuis R, Rozemuller AJ, Scheper W, et al. The pre- Vol.13, No.1 | 2015 | hypothesisjournal.com HYPOTHESIS Protein amplification in neurodegenerative disorders 5/5 Re eclampsia gene STOX1 controls a conserved path- 21 Gründemann J, Schlaudraff F, Haeckel O, Liss B. 27 Karapetyan YE, Sferrazza GF, Zhou M, Ottenberg G, way in placenta and brain upregulated in late-on- Elevated alpha-synuclein mRNA levels in individual Spicer T, Chase P, et al. Unique drug screening set Alzheimer's disease. J Alzheimers Dis. 2010;19: UV-laser-microdissected dopaminergic substantia approach for prion diseases identifies tacrolimus 673-9. nigra neurons in idiopathic Parkinson's disease. and astemizole as antiprion agents. Proc Natl Acad http://dx.doi.org/10.3233/JAD-2010-1265 Nucleic Acids Res. 2008;36:e38. Sci U S A. 2013;110:7044-49. 16 van Abel D, Michel O, Veerhuis R, Jacobs M, http://dx.doi.org/10.1093/nar/gkn084 http://dx.doi.org/10.1073/pnas.1303510110 van Dijk M, Oudejans CB. Direct downregulation of 22 Kudo W, Lee HP, Zou WQ, Wang X, Perry G, Zhu CNTNAP2 by STOX1A is associated with Alzheimer's X, et al. Cellular prion protein is essential for oligo- disease. J Alzheimers Dis. 2012;31:793-800. meric amyloid-b-induced neuronal cell death. Hum http://dx.doi.org/10.3233/JAD-2012-120472 Mol Genet. 2012;21:1138-44. 17 McKee AC, Stein TD, Nowinski CJ, Stern RA, http://dx.doi.org/10.1093/hmg/ddr542 Daneshvar DH, Alvarez VE, et al. The spectrum of 23 Rial D, Piermartiri TC, Duarte FS, Tasca CI, Walz disease in chronic traumatic encephalopathy. Brain. R, Prediger RD. Overexpression of cellular prion 2013;136(Pt 1): 43-64. Erratum in: Brain. 2013 protein (PrP(C)) prevents cognitive dysfunction and Oct;136(Pt 10):e255. apoptotic neuronal cell death induced by amyloid- http://dx.doi.org/10.1093/brain/aws307 b (Ab1-40) administration in mice. Neuroscience. 18 Sephton CF, Cenik C, Kucukural A, Dammer EB, 2012;215:79-89. Cenik B, Han Y, et al. Identification of neuronal RNA http://dx.doi.org/10.1016/j.neuroscience.2012.04.034 targets of TDP-43-containing ribonucleoprotein 24 Whitehouse IJ, Miners JS, Glennon EB, Kehoe complexes. J Biol Chem. 2011; 286:1204-15. PG, Love S, Kellett KA, Hooper NM. Prion protein http://dx.doi.org/10.1074/jbc.M110.190884 is decreased in Alzheimer's brain and inversely cor- 19 Parker SJ, Meyerowitz J, James JL, Liddell JR, relates with BACE1 activity, amyloid-b levels and Crouch PJ, Kanninen KM, White AR. Endogenous Braak stage. PLoS One. 2013;8:e59554. TDP-43 localized to stress granules can subse- http://dx.doi.org/10.1371/journal.pone.0059554 quently form protein aggregates. Neurochem Int. 25 Rybner C, Hillion J, Sahraoui T, Lanotte M, Botti 2012;60:415-24. J. All-trans retinoic acid down-regulates prion pro- http://dx.doi.org/10.1016/j.neuint.2012.01.019 tein expression independently of granulocyte matu- 20 Atlas R, Behar L, Sapoznik S, Ginzburg I. ration. Leukemia 2002;16:940-8. Dynamic association with polysomes during P19 26 Bate C, Tayebi M, Diomede L, Salmona M, neuronal differentiation and an untranslated-region- Williams A. Glimepiride reduces the expression dependent translation regulation of the tau mRNA by of PrPc, prevents PrPsc formation and protects the tau mRNA-associated proteins IMP1, HuD, and against prion mediated neurotoxicity in cell lines. G3BP1. Neurosci Res. 2007;85:173-83. PLoS One. 2009;4:e8221. http://dx.doi.org/10.1371/journal.pone.0008221 HYPOTHESIS Vol.13, No.1 | 2015 | hypothesisjournal.com