title: Structural and kinetic analysis of protein-aggregate strains in vivo using binary epitope mapping.
abstract: Despite considerable progress in uncovering the molecular details of protein aggregation in vitro, the cause and mechanism of protein-aggregation disease remain poorly understood. One reason is that the amount of pathological aggregates in neural tissue is exceedingly low, precluding examination by conventional approaches. We present here a method for determination of the structure and quantity of aggregates in small tissue samples, circumventing the above problem. The method is based on binary epitope mapping using anti-peptide antibodies. We assessed the usefulness and versatility of the method in mice modeling the neurodegenerative disease amyotrophic lateral sclerosis, which accumulate intracellular aggregates of superoxide dismutase-1. Two strains of aggregates were identified with different structural architectures, molecular properties, and growth kinetics. Both were different from superoxide dismutase-1 aggregates generated in vitro under a variety of conditions. The strains, which seem kinetically under fragmentation control, are associated with different disease progressions, complying with and adding detail to the growing evidence that seeding, infectivity, and strain dependence are unifying principles of neurodegenerative disease.
authors: Departments of Medical Biosciences and.
authors: Johan
authors: J
authors: Bergh
authors: Departments of Medical Biosciences and.
authors: Per
authors: P
authors: Zetterström
authors: Pharmacology and Clinical Neuroscience, Umeå University, SE-90186 Umeå, Sweden; and.
authors: Peter M
authors: PM
authors: Andersen
authors: Departments of Medical Biosciences and.
authors: Thomas
authors: T
authors: Brännström
authors: Departments of Medical Biosciences and.
authors: Karin S
authors: KS
authors: Graffmo
authors: Departments of Medical Biosciences and.
authors: P Andreas
authors: PA
authors: Jonsson
authors: Department of Biochemistry and Biophysics, Arrhenius Laboratory for Natural Sciences, Stockholm University, SE-10691 Stockholm, Sweden.
authors: Lisa
authors: L
authors: Lang
authors: Department of Biochemistry and Biophysics, Arrhenius Laboratory for Natural Sciences, Stockholm University, SE-10691 Stockholm, Sweden.
authors: Jens
authors: J
authors: Danielsson
authors: Department of Biochemistry and Biophysics, Arrhenius Laboratory for Natural Sciences, Stockholm University, SE-10691 Stockholm, Sweden.
authors: Mikael
authors: M
authors: Oliveberg
authors: Departments of Medical Biosciences and stefan.marklund@medbio.umu.se.
authors: Stefan L
authors: SL
authors: Marklund
mesh_terms: D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism; D018604:Epitope Mapping / Q000379:methods*; D000939:Epitopes / Q000737:chemistry; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D019636:Neurodegenerative Diseases / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D055503:Protein Multimerization; D011506:Proteins / Q000737:chemistry*; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000737:chemistry / Q000235:genetics*; D000072105:Superoxide Dismutase-1
chemical_list: D000939:Epitopes; D011506:Proteins; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: amyotrophic lateral sclerosis; neurodegeneration; protein aggregation; strain; transgenic mice