title: The contrasting effect of macromolecular crowding on amyloid fibril formation.
abstract: BACKGROUND
  Amyloid fibrils associated with neurodegenerative diseases can be considered biologically relevant failures of cellular quality control mechanisms. It is known that in vivo human Tau protein, human prion protein, and human copper, zinc superoxide dismutase (SOD1) have the tendency to form fibril deposits in a variety of tissues and they are associated with different neurodegenerative diseases, while rabbit prion protein and hen egg white lysozyme do not readily form fibrils and are unlikely to cause neurodegenerative diseases. In this study, we have investigated the contrasting effect of macromolecular crowding on fibril formation of different proteins.
  
  
  RESULTS
  As revealed by assays based on thioflavin T binding and turbidity, human Tau fragments, when phosphorylated by glycogen synthase kinase-3β, do not form filaments in the absence of a crowding agent but do form fibrils in the presence of a crowding agent, and the presence of a strong crowding agent dramatically promotes amyloid fibril formation of human prion protein and its two pathogenic mutants E196K and D178N. Such an enhancing effect of macromolecular crowding on fibril formation is also observed for a pathological human SOD1 mutant A4V. On the other hand, rabbit prion protein and hen lysozyme do not form amyloid fibrils when a crowding agent at 300 g/l is used but do form fibrils in the absence of a crowding agent. Furthermore, aggregation of these two proteins is remarkably inhibited by Ficoll 70 and dextran 70 at 200 g/l.
  
  
  CONCLUSIONS
  We suggest that proteins associated with neurodegenerative diseases are more likely to form amyloid fibrils under crowded conditions than in dilute solutions. By contrast, some of the proteins that are not neurodegenerative disease-associated are unlikely to misfold in crowded physiological environments. A possible explanation for the contrasting effect of macromolecular crowding on these two sets of proteins (amyloidogenic proteins and non-amyloidogenic proteins) has been proposed.
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Ma
authors.forename: Jun-Bao
authors.initials: JB
authors.lastname: Fan
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhou
authors.forename: Bing-Rui
authors.initials: BR
authors.lastname: Zhou
authors.forename: Sheng-Rong
authors.initials: SR
authors.lastname: Meng
authors.forename: Ji-Ying
authors.initials: JY
authors.lastname: Hu
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Yi
authors.initials: Y
authors.lastname: Liang
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D000818:Animals; D052160:Benzothiazoles; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008958:Models, Molecular; D009113:Muramidase / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry; D010766:Phosphorylation / Q000187:drug effects; D011108:Polymers / Q000494:pharmacology*; D011328:Prions / Q000737:chemistry; D055503:Protein Multimerization / Q000187:drug effects*; D017433:Protein Structure, Secondary; D011817:Rabbits; D013844:Thiazoles / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry
chemical_list: D000682:Amyloid; D052160:Benzothiazoles; D010446:Peptide Fragments; D011108:Polymers; D011328:Prions; D013844:Thiazoles; D016875:tau Proteins; C009462:thioflavin T; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D009113:Muramidase