title: Familial Parkinson disease mutations influence α-synuclein assembly.
abstract: Lewy bodies composed of aggregates of α-synuclein (αS) in the brain are the main histopathological features of Lewy body diseases (LBD) such as Parkinson's disease and dementia with Lewy bodies. Mutations such as E46K, A30P and A53T in the αS gene cause autosomal dominant LBD in a number of kindreds. Although these mutations accelerate fibril formation, their precise effects at early stages of the αS aggregation process remain unknown. To answer this question, we examined the aggregation including monomer conformational dynamics and oligomerization of the E46K, A30P, A53T and A30P/A53T mutations and wild type (WT) using thioflavin S assay, circular dichroism spectroscopy, photo-induced cross-linking of unmodified proteins, electron microscopy, and atomic force microscopy. Relative to WT αS, E46K αS accelerated the kinetics of the secondary structure change and oligomerization, whereas A30P αS decelerated them. These effects were reflected in changes in average oligomer size. The mutant oligomers of E46K αS functioned as fibril seeds significantly more efficiently than those of WT αS, whereas the mutant oligomers of A30P αS were less efficient. Our results that mutations of familial LBD had opposite effects at early stages of αS assembly may provide new insight into the molecular mechanisms of LBD.
authors.affiliation: Department of Neurology and Neurobiology and Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Ono
authors.forename: Tokuhei
authors.initials: T
authors.lastname: Ikeda
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Takasaki
authors.forename: Masahito
authors.initials: M
authors.lastname: Yamada
mesh_terms: D000595:Amino Acid Sequence; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D020961:Lewy Body Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D018625:Microscopy, Atomic Force; D008969:Molecular Sequence Data; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D017354:Point Mutation / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000502:physiology; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein