Common features at the start of the neurodegeneration cascade.
Amyloidogenic neurodegenerative diseases are incurable conditions with high social impact that are typically caused by specific, largely disordered proteins. However, the underlying molecular mechanism remains elusive to established techniques. A favored hypothesis postulates that a critical conformational change in the monomer (an ideal therapeutic target) in these "neurotoxic proteins" triggers the pathogenic cascade. We use force spectroscopy and a novel methodology for unequivocal single-molecule identification to demonstrate a rich conformational polymorphism in the monomer of four representative neurotoxic proteins. This polymorphism strongly correlates with amyloidogenesis and neurotoxicity: it is absent in a fibrillization-incompetent mutant, favored by familial-disease mutations and diminished by a surprisingly promiscuous inhibitor of the critical monomeric β-conformational change, neurotoxicity, and neurodegeneration. Hence, we postulate that specific mechanostable conformers are the cause of these diseases, representing important new early-diagnostic and therapeutic targets. The demonstrated ability to inhibit the conformational heterogeneity of these proteins by a single pharmacological agent reveals common features in the monomer and suggests a common pathway to diagnose, prevent, halt, or reverse multiple neurodegenerative diseases.
Instituto Cajal, IC-CSIC & Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
Rubén
R
Hervás
Javier
J
Oroz
Albert
A
Galera-Prat
Oscar
O
Goñi
Alejandro
A
Valbuena
Andrés M
AM
Vera
Angel
A
Gómez-Sicilia
Fernando
F
Losada-Urzáiz
Vladimir N
VN
Uversky
Margarita
M
Menéndez
Douglas V
DV
Laurents
Marta
M
Bruix
Mariano
M
Carrión-Vázquez
D000595:Amino Acid Sequence; D058227:Amyloidogenic Proteins / Q000737:chemistry*; D000818:Animals; D001696:Biomechanical Phenomena; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics; D003001:Cloning, Molecular; D006801:Humans; D008969:Molecular Sequence Data; D036103:Nanotechnology; D009391:Nephelometry and Turbidimetry; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000473:pathology*; D009498:Neurotoxins / Q000737:chemistry* / Q000235:genetics; D010454:Peptide Termination Factors / Q000737:chemistry / Q000235:genetics; D010957:Plasmids / Q000737:chemistry / Q000235:genetics; D020815:Polyproteins / Q000737:chemistry; D015202:Protein Engineering / Q000379:methods*; D055550:Protein Stability; D017433:Protein Structure, Secondary; D058767:Protein Unfolding; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics; D013057:Spectrum Analysis / Q000379:methods; D013816:Thermodynamics; D050988:Vesicle-Associated Membrane Protein 2 / Q000737:chemistry / Q000235:genetics; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics
D058227:Amyloidogenic Proteins; D002352:Carrier Proteins; D009498:Neurotoxins; D010454:Peptide Termination Factors; D020815:Polyproteins; C497604:SNCA protein, human; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C494706:Vamp2 protein, rat; D050988:Vesicle-Associated Membrane Protein 2; D051844:alpha-Synuclein