Double-stranded DNA stimulates the fibrillation of alpha-synuclein in vitro and is associated with the mature fibrils: an electron microscopy study.
Filamentous aggregates formed by alpha-synuclein are a prominent and presumably key etiological factor in Parkinson's and other neurodegenerative diseases characterized by motor disorders. Numerous studies have demonstrated that various environmental and intracellular factors affect the fibrillation properties of alpha-synuclein, e.g. by accelerating the process of assembly. Histones, the major component and constituent of chromatin, interact specifically with alpha-synuclein and enhance its fibrillation significantly. Here, we report that another component of chromatin, double-stranded DNA (dsDNA), either linear or supercoiled, also interacts with wild-type alpha-synuclein, leading to a significant stimulation of alpha-synuclein assembly into mature fibrils characterized by a reduced lag phase. In general, the morphology of the fibrils remains unchanged in the presence of linear dsDNA. Electron microscopy reveals that DNA forms various types of complexes upon association with the fibrils at their surface without distortion of the double-helical structure. The existence of these complexes was confirmed by the electrophoresis, which also demonstrated that a fraction of the associated DNA was resistant to digestion by restriction endonucleases. Fibrils assembled from the alpha-synuclein mutants A30P and A53T and the C-terminally truncated variants (encoding amino acid residues 1-108 or 1-124) also form complexes with linear dsDNA. Possible mechanisms and implications of dsDNA-alpha-synuclein interactions are discussed.
Cherny
Dmitry
D
Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, D-37077 Goettingen, Germany.
Hoyer
Wolfgang
W
Subramaniam
Vinod
V
Jovin
Thomas M
TM
D000818:Animals; D004247:DNA / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D009690:Nucleic Acid Conformation; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D051843:Synucleins; D051844:alpha-Synuclein
D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D004247:DNA