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Natural Inhibitors of Amyloid Aggregation

Paolo Tortora and Francesco A. Aprile

Int. J. Mol. Sci. 24(17), 13310 (2023). 10.3390/ijms241713310 - Editorial.

α-Synuclein Aggregation is Triggered by Oligomeric Amyloid-β 42 via Heterogeneous Primary Nucleation

Devkee M. Vadukul, Marcell Papp, Rebecca J. Thrush, Jielei Wang, Yiyun Jin, Paolo Arosio, Francesco A. Aprile

J. Am. Chem. Soc.145, 33, 18276–18285 (2023). 10.1021/jacs.3c03212.

Unveiling the Rational Development of Stimuli-Responsive Silk Fibroin-Based Ionogel Formulations

Talia A. Shmool, Laura K. Martin, Andreas Jirkas, Richard P. Matthews, Anna P. Constantinou, Devkee M. Vadukul, Theoni K. Georgiou, Francesco A. Aprile, and Jason P. Hallett

Chem. Mater. 35, 15, 5798–5808 (2023). 10.1021/acs.chemmater.3c00303.

Galectin-3 shapes toxic alpha-synuclein strains in Parkinson's disease

Juan García-Revilla, Antonio Boza-Serrano, Yiyun Jin, Devkee M. Vadukul, Jesús Soldán-Hidalgo, Lluís Camprubí-Ferrer, Marta García-Cruzado, Isak Martinsson, Oxana Klementieva, Rocío Ruiz, Francesco A. Aprile, Tomas Deierborg, José L Venero. 

Acta Neuropathol. 146, 51-75 (2023). 10.1007/s00401-023-02585-x.


An antibody scanning method for the detection of α-synuclein oligomers in the serum of Parkinson's disease patients.

Klara Kulenkampff, Derya Emin, Roxine Staats, Yu P. Zhang , Laila Sakhnini, Antonina Kouli, Oded Rimon, Evgeniia Lobanova, Caroline H. Williams-Gray, Francesco A. Aprile, Pietro Sormanni, David Klenerman, Michele Vendruscolo. 

Chem. Sci. 13, 13815-13828 (2022). 10.1039/D2SC00066K 

A Facile Method to Produce N-Terminally Truncated α-Synuclein.

Rebecca J. Thrush, Devkee M. Vadukul, Francesco A. Aprile. 

Front. Neurosci. 16:881480 (2022). 10.3389/fnins.2022.881480

A Chemical Mutagenesis Approach to Insert Post-Translational Modifications in Aggregation-Prone Proteins.

Ying Ge, Athina Masoura, Jingzhou Yang, Francesco A. Aprile. 

ACS Chem. Neurosci. 13, 12, 1714-1718 (2022). 10.1021/acschemneuro.2c00077


Man does not live by intrinsically unstructured proteins alone: The role of structured regions in aggregation.

Aprile FA, Temussi PA, Pastore A. 

BioEssays. 2100178 (2021). 10.1002/bies.202100178

The cellular modifier MOAG-4/SERF drives amyloid formation through charge complementation.

Pras A, Houben B, Aprile FA, Seinstra R, Gallardo R, Janssen L, Hogewerf W, Gallrein C, De Vleeschouwer M, Mata-Cabana A, Koopman M, Stroo E, De Vries M, Edwards S, Kirstein J, Vendruscolo M, Falsone SF, Rousseau F, Schymkowitz J, Nollen EAA.

EMBO J. e107568 (2021).

The binding of the small heat-shock protein αB-crystallin to fibrils of α-synuclein is driven by entropic forces.

Modulation of Amyloid-β Aggregation by Metal Complexes with a Dual Binding Mode and Their Delivery across the Blood-Brain Barrier Using Focused Ultrasound

Scheidt T, Carozza JA, Kolbe CC, Aprile FA, Tkachenko O, Bellaiche MMJ, Meisl G, Peter Q, Herling TW, Ness S, Cruz MC, Benesch JLP, Vendruscolo M, Dobson CM, Arosio P, Knowles TPJ.

Proc. Natl. Acad. Sci. U.S.A. 118, e2108790118 (2021). 10.1073/pnas.2108790118

The Diagnostic Potential of Amyloidogenic Proteins

Chan TG, Ruehl CL, Morse SV, Simon M, Rakers V, Watts H, Aprile FA, Choi JJ, Vilar R.

Chem. Sci. 12, 9485-9493 (2021).10.1039/d1sc02273c

Jin Y, Vadukul DM, Gialama D, Ge Y, Thrush R, White JT, Aprile FA

Int. J. Mol. Sci. 22, 4128 (2021). doi:10.3390/ijms22084128

Comparative Studies in the A30P and A53T α-Synuclein C. elegans Strains to Investigate the Molecular Origins of Parkinson's Disease

Perni M, Van Der Goot A, Limbocker R, Van Ham T, Aprile FA, Xu C, Flamgeier P, Thijssen K, Sormanni P, Fusco G, Chen SW, Calla PK, Kirkegaard JB, Laine R, Ma KY, Muller MBD, Sinnige T, Kumita JK, Cohen SIA, Seinstra R, Kaminski Schierle GS, Kaminski CF, Barbut D, De Simone A, Knowles TPJ, Zasloff MA, Nollen E, Vendruscolo M, Dobson CM. Front. Cell Dev. Biol. 9:552549 (2021). 10.3389/fcell.2021.552549

Rationally Designed Bicyclic Peptides Prevent the Conversion of Aβ42 Assemblies into Fibrillar Structures

Ikenoue T, Aprile FA, Sormanni P, Vendruscolo MFront. Neurosci. 15, 623097 (2021). 10.3389/fnins.2021.623097

Systematic Activity Maturation of a Single-Domain Antibody with Non-canonical Amino Acids through Chemical Mutagenesis

Lindstedt PR, Aprile FA, Sormanni P, Rakoto R, Dobson CM, Bernardes GJL, Vendruscolo MCell Chem. Biol. 28, 70-77 (2021). doi:10.1016/j.chembiol.2020.11.002


Small Molecule Sequestration of Amyloid-β as a Drug Discovery Strategy for Alzheimer’s Disease.

Heller GT, Aprile FA, Michaels TCT, Limbocker R, Perni M, Ruggeri FS, Mannini B, Löhr T, Bonomi M, De Simone A, Felli IC, Pierattelli R, Knowles TPJ, Dobson CM, and Vendruscolo M. 

Sci. Adv. 6, eabb5924 (2020). 10.1126/sciadv.abb5924

A rationally designed bicyclic peptide remodels Aβ42 aggregation in vitro and reduces its toxicity in a worm model of Alzheimer's disease

Ikenoue T, Aprile FA, Sormanni P, Ruggeri FS, Perni M, Heller GT, Haas CP, Middel C, Limbocker R, Mannini B, Michaels TCT, Knowles TPJ, Dobson CM, Vendruscolo M
Sci. Rep. 10,15280 (2020) doi:10.1038/s41598-020-69626-3

Rationally Designed Antibodies as Research Tools to Study the Structure–Toxicity Relationship of Amyloid-β Oligomers

Limbocker R*, Mannini B, Cataldi R, Chhangur S, Wright AK, Kreiser RP, Albright JA, Chia S, Habchi J, Sormanni P, Kumita JR, Ruggeri FS, Dobson CM, Chiti F, Aprile FA*, Vendruscolo M*
Int. J. Mol. Sci. 21(12), 4542 (2020) doi:10.3390/ijms21124542

Rational design of a conformation-specific antibody for the quantification of Aβ oligomers

Aprile FA*, Sormanni P, Podpolny M, Chhangur S, Needham L-M, Ruggeri FS, Perni M, Limbocker R, Heller GT, Sneideris T, Scheidt T, Mannini B, Habchi J, Lee SF, Salinas PC, Knowles TPJ, Dobson CM, Vendruscolo M*
Proc Natl Acad Sci U S A 117 (24), 13509-13518 (2020); DOI: 10.1073/pnas.1919464117


C. elegans expressing D76N β2-microglobulin: a model for in vivo screening of drug candidates targeting amyloidosis.

Faravelli G, Raimondi S, Marchese L, Partridge FA, Soria C, Mangione P, Canetti D, Perni M, Aprile FA, Zorzoli I, Di Schiavi E, Lomas DA, Bellotti V, Sattelle DB, and Giorgietti S.
Sci. Rep. 9, 19960 (2019) doi: 10.1038/s41598-019-56498-5

Soluble aggregates present in a cerebrospinal fluid change in size and mechanism of toxicity during Alzheimer's disease progression

De S, Whiten DR, Ruggeri FS, Hughes C, Rodrigues M, Sideris DI, Taylor CG, Aprile FA, Muyldermans S, Knowles TPJ, Vendruscolo M, Bryant CE, Blennow K, Skoog I, Kern S, Zetterberg H, and Klenerman D.
Acta Neuropathol. Commun. 7, 120 (2019) doi: 10.1186/s40478-019-0777-4

Enhancement of the Anti-Aggregation Activity of a Molecular Chaperone Using a Rationally Designed Post-Translational Modification

Philip LR, Aprile FA, Matos MJ, Perni M; Bertoldo JB, Bernardim B, Quentin P, Jiménez-Osés G, Gonzalo Knowles TPJ; Dobson CM; Corzana F; Vendruscolo M, and Bernardes G.
ACS Cent. Sci. 5, 1417-1424 (2019) doi: 10.1021/acscentsci.9b00467

Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms

De S*, Wirthensohn DC*, Flagmeier P*, Hughes C*, Aprile FA*, Ruggeri FS*, Whiten DR, Emin D, Xia Z, Varela JA, Sormanni P, Kundel F, Knowles TPJ, Dobson CM, Bryant C, Vendruscolo M, and Klenerman D.
Nat. Commun. 10, 1541 (2019) doi: 10.1038/s41467-019-09477-3


Third generation antibody discovery methods: in silico rational design

Sormanni P, Aprile FA, and Vendruscolo M.
Chem. Soc. Rev. 47, 9137-9157 (2018) doi: 10.1039/c8cs00523k

Automated behavioural analysis of large C. elegans populations using a wide field of view tracking platform​

Perni M, Casford S, Aprile FA, Nollen EAA, Knowles TPJ, Vendruscolo M, and Dobson CM.
J. Vis. Exp. 141, e58643 (2018) doi: 10.3791/58643

Targeting amyloid aggregation: an overview of strategies and mechanisms

Giorgetti S, Greco C, Tortora P, and Aprile FA.
Int. J. Mol. Sci. 19, 2677 (2018) doi: 10.3390/ijms19092677

Multistep inhibition of α-synuclein aggregation and toxicity in vitro and in vivo by trodusquemine

Perni M, Flagmeier P, Limbocker R, Cascella R, Aprile FA, Galvagnion C, Heller GT, Meisl G, Chen SW, Kumita JR, Challa PK, Kirkegaard JB, Cohen SIA, Mannini B, Barbut D, Nollen EAA, Cecchi C, Cremades N, Knowles TPJ, Chiti F, Zasloff M, VendruscoloM, and Dobson CM.
ACS Chem. Biol. 13, 2308-2319 (2018) doi: 10.1021/acschembio.8b00466.

Cooperative assembly of Hsp70 subdomain clusters

Wright M, Aprile FA, Bellaiche MMJ, Michaels TCT, Muller T, Arosio P, Vendruscolo M, Dobson CM, and Knowles TPJ.
Biochemistry 57, 3641-3649 (2018) doi: 10.1021/acs.biochem.8b00151

A rationally designed Hsp70 variant rescues the aggregation-associated toxicity of human IAPP in cultured pancreatic islet β-cells

Bongiovanni MN, Aprile FA, Sormanni P, and Vendruscolo M.
Int. J. Mol. Sci. 19, 1443 (2018) doi: 10.3390/ijms19051443


Delivery of native proteins into C. elegans using a transduction protocol based on lipid vesicles

Perni M, Aprile FA*, Casford S, Mannini B, Sormanni P, Dobson CM, and Vendruscolo M*.
Sci. Rep. 7, 15045 (2017)  doi: 10.1038/s41598-017-13755-9.

The polyglutamine protein ataxin-3 enables normal growth under heat shock conditions in the methylotrophic yeast Pichia pastoris

Bonanomi M, Roffia V, De Palma A, Lombardi A, Aprile FA, Visentin C, Tortora P, Mauri P, and Regonesi ME. 
Sci. Rep. 7, 13417 (2017) doi: 10.1038/s41598-017-13814-1

Sequence specificity in the entropy-driven binding of a small molecule and a disordered peptide

Heller GT, Aprile FA, Bonomi M, Camilloni C, De Simone A, and Vendruscolo M.
J. Mol. Biol. 429, 2772-2779 (2017) doi: 10.1016/j.jmb.2017.07.016

The molecular chaperones DNAJB6 and Hsp70 cooperate to suppress alpha-synuclein aggregation

Aprile FA, Källstig E, Limorenko G, Vendruscolo M, Ron D, and Hansen C.
Sci. Rep. 7, 9039 (2017) doi: 10.1038/s41598-017-08324-z

Post-expression regioselective mutagenesis reveals a water bridged cysteine–cysteine redox regulation mechanism in bacterial protein tyrosine phosphatases

Bertoldo JB, Rodrigues T, Dunsmore L, Aprile FA, Marques MC, Rosado L, Boutureira O, Steinbrecher TB, Sherman W, Corzana F, Terenzi H, and Bernardes GJL.
Chem 3, 665–677 (2017) doi: 10.1016/j.chempr.2017.07.009

Selective targeting of primary and secondary nucleation pathways in Aβ42 aggregation using a rational antibody scanning method

Aprile FA, Sormanni P, Perni M, Arosio P, Linse S, Knowles TPJ, Dobson CM, and Vendruscolo M.  
Sci. Adv. 3, e1700488 (2017) doi: 10.1126/sciadv.1700488

Methods of probing the interactions between small molecules and disordered proteins

Heller GT, Aprile FA, and Vendruscolo M.
Cell Mol Life Sci. 74, 3225–3243 (2017) doi: 10.1007/s00018-017-2563-41

Identification of a Pol III-associated regulator of small non-coding RNAs that is linked with disease-associated protein aggregation

Sin O, de Jong T, Mata-Cabana A, Kudron M, Zaini A, Aprile FA, Seinstra R, Stroo E, Prins RW, Martineau C, Wang HH, Hogewerf W, Steinhof A, Wanker EE, Vendruscolo M, Calkhoven CF, Reinke V, Guryev V, and Nollen EAA.
Mol. Cell 65, 1096-1108.e6 (2017) doi: 10.1016/j.molcel.2017.02.022

Inhibition of α-synuclein fibril elongation by hsp70 is governed by a kinetic binding competition between α-synuclein species

Aprile FA, Arosio P, Fusco G, Chen SW, Kumita JR, Dhulesia A, Tortora P, Knowles TPJ, and Vendruscolo M, Dobson CM, and Cremades N.
Biochemistry 56, 1177-1180 (2017) doi: 10.1021/acs.biochem.6b01178

A natural product inhibits the initiation of α-synuclein aggregation by displacing it from lipid membranes and suppresses its toxicity

Perni M, Galvagnion C, Alexander SM, Meisl G, Müller MBD, Challa PK, Kirkegaard JB, Flagmeier P, Cohen SIA, Cascella R, Chen SW, Limbocker R, Sormanni P, Heller GT, Aprile FA, Cremades N, Cecchi C, Chiti F, Nollen EAA, Knowles TPJ, Vendruscolo M, Bax A, Zasloff M, and Dobson CM.
Proc Natl Acad Sci U S A 114, E1009-E1017 (2017) doi: 10.1073/pnas.1610586114


Structure of a low-population binding intermediate in protein-RNA recognition

Borkar  AN, Bardaro MF, Camilloni C, Aprile FA, Varani G, and Vendruscolo M.
Proc Natl Acad Sci U S A 113, 7171–7176 (2016) doi: 10.1073/pnas.1521349113

A microfluidic diffusion viscometer for rapid analysis of complex solutions

Arosio P, Hu K, Aprile FA, Müller T, and Knowles TPJ.
Anal. Chem. 88, 3488–3493 (2016) doi: 10.1021/acs.analchem.5b02930

Microfluidic diffusion analysis of the sizes and interactions of proteins under native solution conditions

Arosio P, Muller T, Rajah L, Yates EV, Aprile FA, Zhang Y, Cohen SIA, White DA, Herling TW, De Genst E, Linse S, Vendruscolo M, Dobson CM, and Knowles TPJ.
ACS Nano 10, 333–341 (2016) doi: 10.1021/acsnano.5b04713


Biophysical approaches for the study of interactions between molecular chaperones and protein aggregates

Wright MA, Aprile FA, Arosio P, Vendruscolo M, Dobson CM, and Knowles TPJ.
Chem. Comm. 51, 14425-14234 (2015) doi: 10.1039/c5cc03689e

A rational design strategy for the selective activity enhancement of a molecular chaperone towards a target substrate

Aprile FA, Sormanni P, and Vendruscolo M.
Biochemistry 54, 5103-5112 (2015) doi: 10.1021/acs.biochem.5b00459

Cell surface localised Hsp70 is a cancer specific regulator of clathrin-independent endocytosis 

Nimmervoll B, Chtcheglova LA, Juhasz K, Cremades N, Aprile FA, Sonnleitner A, Hinterdorfer P, Vigh L, Preiner J, and Balogi Z.
FEBS L. 589, 2747-2753 (2015) doi: 10.1016/j.febslet.2015.07.037

Rational design of antibodies targeting specific epitopes within intrinsically disordered proteins 

Sormanni P*,  Aprile FA*, and Vendruscolo M. 
Proc. Natl. Acad. Sci. USA 112, 9902-9907 (2015) doi: 10.1073/pnas.1422401112

Structural characterization of toxic oligomers trapped during α-synuclein fibril formation

Chen SW, Drakulic S, Deas E, Ouberai M, Aprile FA, Arranz R, Ness S, Roodveldt C, Guilliams T, De-Genst EJ, Klenerman D, Wood NW, Knowles TPj, Alfonso C, Rivas G, Abramov AY, Valpuesta JM, Dobson CM, and Cremades N.
Proc Natl Acad Sci U S A 112, E1994-2003 (2015) doi: 10.1073/pnas.1421204112

Structure of a low-population intermediate state in the release of an enzyme product

De Simone A, Aprile FA, Dhulesia A, Dobson CM, and Vendruscolo M.
eLife 4, e02777 (2015) doi: 10.7554/eLife.02777

The structure and dynamics of the lymphocyte function associated antigen-1 I-domain in the inactive state underlie its inside-out/outside-in signalling and allosteric mechanism

Kukic P, Alvin Leung HT, Bemporad F, Aprile FA, Kumita JR, De Simone A, Camilloni C, and Vendruscolo M.
Structure 23, 745-753 (2015) doi: 10.1016/j.str.2014.12.020

The CamSol method of rational design of protein mutants with enhanced solubility

Sormanni P*, Aprile FA*, and Vendruscolo M.
J. Mol. Biol. 427, 478-490 (2015) doi: 10.1016/j.jmb.2014.09.02


NMR characterization of the conformational fluctuations of the human lymphocyte function-associated antigen-1 I-domain

Leung HT, Kukic P, Camilloni C, Bemporad F, De Simone A, Aprile FA, Kumita JR, and Vendruscolo M.
Protein Sci. 23, 1596-1606 (2014) doi: 10.1002/pro.2538


Hsp70 oligomerization is mediated by an interaction between the interdomain linker and the substrate-binding domain

Aprile FA, Dhulesia A, Stengel F, Roodveldt C, Benesch JL, Tortora P, Robinson CV, Salvatella X, Dobson CM, and Cremades N.
PLoS One 8, e67961 (2013) doi: 10.1371/journal.pone.0067961

Nanobodies raised against monomeric α-synuclein distinguish between fibrils at different maturation stages

Guilliams T, El-Turk F, Buell AK, O'Day EM, Aprile FA, Esbjörner EK, Vendruscolo M, Cremades N, Pardon E, Wyns L, Welland ME, Steyaert J, Christodoulou J, Dobson CM, and De Genst E.
J. Mol. Biol. 425, 2397-2411 (2013) doi: 10.1016/j.jmb.2013.01.040


The relationship between aggregation and toxicity of polyglutamine-containing ataxin-3 in the intracellular environment of Escherichia coli

Invernizzi G*, Aprile FA*, Natalello A, Ghisleni A, Penco A, Relini A, Doglia SM, Tortora P, and Regonesi ME.
PLoS One 7, e51890 (2012) doi: 0.1371/journal.pone.0051890
*Authors equally contributed to the work

Direct observation of the interconversion of normal and toxic forms of α-synuclein

Cremades N, Cohen SI, Deas E, Abramov AY, Chen AY, Orte A, Sandal M, Clarke RW, Dunne P, Aprile FA, Bertoncini CW, Wood NW, Knowles TPJ, Dobson CM, and Klenerman D.
Cell 149, 1048-1059 (2012) doi: 10.1016/j.cell.2012.03.037

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