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A Natural Product Inhibits the Initiation of Α-Synuclein Aggregation And

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A Natural Product Inhibits the Initiation of Α-Synuclein Aggregation And Correction NEUROSCIENCE Correction for “A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity,” by Michele Perni, Céline Galvagnion, Alexander Maltsev, Georg Meisl, Martin B. D. Müller, Pavan K. Challa, Julius B. Kirkegaard, Patrick Flagmeier, Samuel I. A. Cohen, Roberta Cascella, Serene W. Chen, Ryan Limboker, Pietro Sormanni, Gabriella T. Heller, Francesco A. Aprile, Nunilo Cremades, Cristina Cecchi, Fabrizio Chiti, Ellen A. A. Nollen, Tuomas P. J. Knowles, Michele Vendruscolo, Adriaan Bax, Michael Zasloff, and Christopher M. Dobson, which appeared in issue 6, February 7, 2017, of Proc Natl Acad Sci USA (114:E1009– E1017; first published January 17, 2017; 10.1073/pnas.1610586114). The authors note that Ryan Limbocker’s name incorrectly appeared as Ryan Limboker. The corrected author line appears below. The online version has been corrected. Michele Perni, Céline Galvagnion, Alexander Maltsev, Georg Meisl, Martin B. D. Müller, Pavan K. Challa, Julius B. Kirkegaard, Patrick Flagmeier, Samuel I. A. Cohen, Roberta Cascella, Serene W. Chen, Ryan Limbocker, Pietro Sormanni, Gabriella T. Heller, Francesco A. Aprile, Nunilo Cremades, Cristina Cecchi, Fabrizio Chiti, Ellen A. A. Nollen, Tuomas P. J. Knowles, Michele Vendruscolo, Adriaan Bax, Michael Zasloff, and Christopher M. Dobson www.pnas.org/cgi/doi/10.1073/pnas.1701964114 CORRECTION www.pnas.org PNAS | March 21, 2017 | vol. 114 | no. 12 | E2543 Downloaded by guest on September 28, 2021 A natural product inhibits the initiation of α-synuclein PNAS PLUS aggregation and suppresses its toxicity Michele Pernia,b, Céline Galvagniona,1, Alexander Maltsevc, Georg Meisla, Martin B. D. Müllera,b, Pavan K. Challaa, Julius B. Kirkegaardd, Patrick Flagmeiera, Samuel I. A. Cohena, Roberta Cascellae, Serene W. Chena, Ryan Limbockera, Pietro Sormannia, Gabriella T. Hellera, Francesco A. Aprilea, Nunilo Cremadesf, Cristina Cecchie, Fabrizio Chitie, Ellen A. A. Nollenb, Tuomas P. J. Knowlesa, Michele Vendruscoloa,2, Adriaan Baxc,2, Michael Zasloffg,2, a,2 and Christopher M. Dobson SEE COMMENTARY aDepartment of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom; bUniversity Medical Centre Groningen, European Research Institute for the Biology of Aging, University of Groningen, Groningen 9713 AV, The Netherlands; cLaboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; dDepartment of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge CB3 0WA, United Kingdom; eDepartment of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy; fBiocomputation and Complex Systems Physics Institute (BIFI)-Joint Unit BIFI-IQFR (CSIC), University of Zaragoza, 50018 Zaragoza, Spain; and gMedStar–Georgetown Transplant Institute, Georgetown University School of Medicine, Washington, DC 20010 Edited by Gregory A. Petsko, Weill Cornell Medical College, New York, NY, and approved December 5, 2016 (received for review June 29, 2016) The self-assembly of α-synuclein is closely associated with Parkinson’s growth factor-dependent pathways and thus has emerged as a drug disease and related syndromes. We show that squalamine, a natural candidate for the treatment of cancer and macular degeneration (15, product with known anticancer and antiviral activity, dramatically 16). In the present context, our choice of studying squalamine was affects α-synuclein aggregation in vitro and in vivo. We elucidate prompted by the observation that this molecule is able to enter the mechanism of action of squalamine by investigating its interaction eukaryotic cells and displace proteins that are bound to the cyto- with lipid vesicles, which are known to stimulate nucleation, and find plasmic face of plasma membranes (17–19),suggestingthatitmay that this compound displaces α-synuclein from the surfaces of such influence the initiation of the aggregation of α-synuclein (12). Indeed vesicles, thereby blocking the first steps in its aggregation process. We squalamine has been referred to as a “cationic lipid” (18) as it carries a also show that squalamine almost completely suppresses the toxicity net positive charge and shows a high affinity for anionic phospholipids α of -synuclein oligomers in human neuroblastoma cells by inhibiting (20) of the type that nucleates the aggregation of α-synuclein, thereby their interactions with lipid membranes. We further examine the ef- reducing the negative charge of themembranesurfacetowhichitis fects of squalamine in a Caenorhabditis elegans strain overexpressing bound (18, 21) without significantly disrupting the integrity of lipid α-synuclein, observing a dramatic reduction of α-synuclein aggrega- surfaces (18). In analogy, it has recently been shown that a homolo- tion and an almost complete elimination of muscle paralysis. These gous protein, β-synuclein, can inhibit α-synuclein lipid-induced aggre- findings suggest that squalamine could be a means of therapeutic gation via a competitive binding at the surface of lipid vesicles (22). intervention in Parkinson’s disease and related conditions. NEUROSCIENCE Parkinson’s disease | protein aggregation | amyloid formation | Significance toxic oligomers | drug development Parkinson’s disease is characterized by the presence in brain tissues α he aggregation of α-synuclein (Fig. 1A), an intrinsically dis- of aberrant aggregates primarily formed by the protein -synuclein. Tordered protein expressed at high levels in the brain, is It has been difficult, however, to identify compounds capable of closely associated with the pathogenesis of a variety of neuro- preventing the formation of such deposits because of the com- α degenerative disorders, collectively known as α-synucleino- plexity of the aggregation process of -synuclein. By exploiting pathies, including Parkinson’s disease (PD), dementia with Lewy recently developed highly quantitative in vitro assays, we identify a α bodies (DLB), and multiple-system atrophy (MSA) (1–7). It has compound, squalamine, that blocks -synuclein aggregation, and been exceptionally challenging, however, to develop effective characterize its mode of action. Our results show that squalamine, α strategies to suppress the formation of α-synuclein aggregates by competing with -synuclein for binding lipid membranes, spe- and their associated toxicity (8, 9), because the mechanism of cifically inhibits the initiation of the aggregation process of α α aggregation of this protein is extremely complex and highly de- -synuclein and abolishes the toxicity of -synuclein oligomers in ’ pendent on environmental factors, such as pH, temperature, and neuronal cells and in an animal model of Parkinson sdisease. contact with surfaces (10). In particular, it is well established that Author contributions: M.P., E.A.A.N., T.P.J.K., M.V., A.B., M.Z., and C.M.D. designed re- phospholipid binding can accelerate fibril formation (11); moreover, search; M.P., C.G., A.M., G.M., M.B.D.M., P.K.C., J.B.K., P.F., R.C., R.L., P.S., G.T.H., F.A.A., it has recently been shown that such acceleration occurs through the C.C., F.C., T.P.J.K., A.B., and M.Z. performed research; P.K.C., S.W.C., N.C., and E.A.A.N. enhancement of the initial primary nucleation step in the aggrega- contributed new reagents/analytic tools; M.P., C.G., A.M., G.M., P.K.C., J.B.K., P.F., S.I.A.C., tion process (12). In the light of this information, we decided to R.C., R.L., P.S., C.C., F.C., E.A.A.N., T.P.J.K., A.B., M.Z., and C.M.D. analyzed data; and M.P., investigate whether compounds capable of altering the binding of T.P.J.K., M.V., A.B., M.Z., and C.M.D. wrote the paper. α-synuclein to lipid membranes could be effective in inhibiting its Conflict of interest statement: M.Z. is the inventor on a patent application that has been filed related to the compound described in this paper. The other authors declare no aggregation. This study was stimulated by our recent finding that a conflict of interest. small molecule, bexarotene, can suppress significantly the primary This article is a PNAS Direct Submission. nucleation reaction that initiates the production of the Aβ ag- 42 Freely available online through the PNAS open access option. gregates linked with Alzheimer’s disease (AD) and reduces the as- sociated toxicity in a Caenorhabditis elegans model of this disease (13). See Commentary on page 1223. 1 In the present work, we have focused on one particular com- Present address: German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, B Germany, and Institute of Physical Biology, Heinrich Heine Universität, Universitätsstr. pound, squalamine (Fig. 1 ), an antimicrobial aminosterol origi- 1, 40225 Duesseldorf, Germany. Squalus acanthias nally discovered in 1993 in the dogfish shark, 2To whom correspondence may be addressed. Email: [email protected], [email protected], (14). This small molecule, now prepared synthetically (see [email protected], or [email protected]. SI Materials and Methods for details), has been found to This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. have pharmacological activity in endothelial cells by inhibiting 1073/pnas.1610586114/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1610586114 PNAS | Published online January 17, 2017 | E1009–E1017 A N-terminus C-terminus MDVFMKGLSKAKEGVVAAAEKTKQGVAEAAGKTKEGVLYVGSKTKEGVVHGVATVAEKTKEQVTNVGGAVVTGVTAVAQKTVEGAGSIAAATGFVKKDQLGKNEEGAPQEGILEDMPVDPDNEAYEMPSEEGYQDYEPEA 1866 25 98107 140 -3 B C 0 Unbound NH2 ) x 10 -5 -1 0μM -10 10μM 20μM HN dmol -15 30μM 2 40μM HN H -20 H O 50μM H O S O 60μM H H -25 OH 70μM OH Membrane bound ] (deg cm -30 θ [ 200 210 220 230 240 250 Wavelength (nm) -3 D 0 E 1 C-Terminal residue ) x 10 -5 -1 0.8 -10 Central Residue 0 M1 0.6 dmol G86 2 -15 I / 0.4 A107 -20 N-Terminal residue -25 No SUVs 0.2 ] (deg cm -30 0 222 0102030 40 50 60 70 0 50 100 150 200 250 θ [ [Squalamine] (μM) [Squalamine] (μM) F Unbound 1.0 0.8 176 M 0 0.6 144 M I / 0.4 112 M 96 M 0.2 64 M 0 M Membrane bound 0.0 1 6 25 98 140 Residue Number Fig.
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