Beta-synuclein inhibits formation of alpha-synuclein protofibrils: a possible therapeutic strategy against Parkinson's disease.
Parkinson's disease (PD) is an age-associated and progressive movement disorder that is characterized by dopaminergic neuronal loss in the substantia nigra and, at autopsy, by fibrillar alpha-synuclein inclusions, or Lewy bodies. Despite the qualitative correlation between alpha-synuclein fibrils and disease, in vitro biophysical studies strongly suggest that prefibrillar alpha-synuclein oligomers, or protofibrils, are pathogenic. Consistent with this proposal, transgenic mice that express human alpha-synuclein develop a Parkinsonian movement disorder concurrent with nonfibrillar alpha-synuclein inclusions and the loss of dopaminergic terminii. Double-transgenic progeny of these mice that also express human beta-synuclein, a homologue of alpha-synuclein, show significant amelioration of all three phenotypes. We demonstrate here that beta- and gamma-synuclein (a third homologue that is expressed primarily in peripheral neurons) are natively unfolded in monomeric form, but structured in protofibrillar form. Beta-synuclein protofibrils do not bind to or permeabilize synthetic vesicles, unlike protofibrils comprising alpha-synuclein or gamma-synuclein. Significantly, beta-synuclein inhibits the generation of A53T alpha-synuclein protofibrils and fibrils. This finding provides a rationale for the phenotype of the double-transgenic mice and suggests a therapeutic strategy for PD.
Park
June-Young
JY
Center for Neurologic Diseases, Brigham and Women's Hospital and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA.
Lansbury
Peter T
PT
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry*; D002942:Circular Dichroism; D006801:Humans; D008027:Light; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism* / Q000628:therapy; D010539:Permeability; D010743:Phospholipids / Q000378:metabolism; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D051843:Synucleins; D051844:alpha-Synuclein; D051846:beta-Synuclein; D051845:gamma-Synuclein
D000682:Amyloid; D009419:Nerve Tissue Proteins; D010743:Phospholipids; C497604:SNCA protein, human; C497607:SNCB protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D051846:beta-Synuclein; D051845:gamma-Synuclein