Challenges in Alzheimer's, Parkinson and Amyotrophic Lateral Sclerosis diseases from experimental (in vitro and in vivo) to theoretical/ computational perspectives
This workshop aims to be a comprehensive, authoritative, critical state-of-the art on protein misfolding and aggregation which is the fundamental cause of more than 20 amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues, with disorders ranging from Alzheimer’s (Aβ and tau), Parkinson (α-synuclein) to amyotrophic lateral sclerosis or ALS (superoxide dismutase, SOD) and type II diabetes (IAPP).
Experimental determination of oligomers is challenging because of their transient natures and requires the development and the use of several innovative biophysical techniques (1-3). Simulations of aggregation at different time and length scales can complement experiment, but requires the development of accurate models ranging from all-atom, coarse-grained to mesoscopic or super-mesoscopic representations (4-9).
Understanding how amyloid aggregates actually become toxic is the challenge in developing a treatment for such diseases. There is evidence from in vitro and in vivo studies indicating crosstalk between different amyloid proteins and interactions between Aβ, tau and α-synuclein promote protein aggregation and accelerate cognitive dysfunction (10).
The central aim of this workshop is to bring together scientists from different disciplines working on different amyloid proteins so as to discuss common and different features between the diseases and their possible links with a critical and an in-depth overview of our current knowledge on Aβ genesis, amyloid oligomers and formation (kinetics and thermodynamics) and toxicity using a very broad range of biophysical and biochemical methods, computer simulations, liquid-liquid phase separation of disordered proteins, in vivo studies and systems biology.
Emphasis will be put on the exploration of novel simulation approaches and experimental techniques to approach aggregation on relevant size and time scales in aqueous solution, interacting with metals, membrane, in a crowded environment and in cells. We focus on Alzheimer and Parkinson diseases that appear to talk together, on type II Diabetes and ALS.
We are confident that this workshop will encourage new collaborations between computational and experimental scientists working on different amyloid proteins and diseases, will identify the main challenges and ignite new ideas allowing ultimately an efficient treatment of all these diseases (10). This is particularly important as there is accumulating pathological evidence that many neurodegenerative diseases are mixed proteinopathies. Copathologies and cross-talks are likely a common feature of aging and neurological disorders, whereby the prevalence of these pathologies ultimately determines the type of disorder development in the aging brain.
The following topics are covered.
1. APP and Abeta genesis
2. Structure determination of amyloid fibrils
3. Exploring meta-stable oligomers
4. Liquid-liquid phase separation of disordered proteins
5. SOD, IAPP and tau proteins
6. Theoretical and computation studies of aggregation
7. Influence of metal ions, membrane and crowding on aggregation
8. Biological chemistry of aggregation and systems biology of neurodegenerative diseases
9. An academic and industrial view of drug discovery.
(1) Eisenberg DS, Sawaya MR., Annu Rev Biochem. 2017,86:69-95.
(2) Qiang W, Yau WM, Lu JX, Collinge J, Tycko R. Nature. 2017,541:217-221.
(3) Fusco G et al. De Simone A., Science. 2017,358:1440-1443.
(4) Robustelli P, Piana S, Shaw DE. PNAS 2018,115:E4758-E4766.
(5) Šarić A, Michaels TCT, Zaccone A, Knowles TPJ, Frenkel D. J Chem Phys. 2016,145(21):211926.
(6) Dominguez L, Foster L, Straub JE, Thirumalai D. PNAS 2016,113(36):E5281-7.
(7) Nasica-Labouze J, Nguyen PH, Sterpone F et al. Derreumaux P. Chem Rev. 2015,115(9):3518-63.
(8) Levine ZA, Shea JE. Curr Opin Struct Biol. 2017,43:95-103.
(9) Bunce SJ et al. Sci Adv. 2019,5(6):eaav8216.
(10) Nguyen PH, Ramamoorthy A, Sahoo BR, Zheng J, Faller P, Straub JE, Dominguez L, Shea JE, Dokholyan NV, De Simone A, Ma B, Nussinov R, Najafi S, Ngo ST, Loquet A, Chiricotto M, Ganguly P, McCarty J, Li MS, Hall C, Wang Y, Miller Y, Melchionna S, Habenstein B, Timr S, Chen J, Hnath B, Strodel B, Kayed R, Lesné S, Wei G, Sterpone F, Doig AJ, Derreumaux P. Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer's Disease, Parkinson's Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis. Chem Rev. 2021 Feb 24;121(4):2545-2647.
Philippe Derreumaux (UPR9080 CNRS) - Organiser
Phuong Nguyen (IBPC and University Paris) - Organiser
Fabio Sterpone (IBPC and University Paris) - Organiser
Birgit Strodel (Research Centre Jülich) - Organiser
Nikolay Dokholyan (Penn State University College of Medicine) - Organiser
Joan-Emma Shea (University of California, Santa Barbara) - Organiser
John E. Straub (Boston University) - Organiser