β-Synuclein Inhibits Formation of α-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 α-synuclein inclusions, or Lewy bodies. Despite the qualitative correlation between α-synuclein fibrils and disease, in vitro biophysical studies strongly suggest that prefibrillar α-synuclein oligomers, or protofibrils, are pathogenic. Consistent with this proposal, transgenic mice that express human α-synuclein develop a Parkinsonian movement disorder concurrent with nonfibrillar α-synuclein inclusions and the loss of dopaminergic terminii. Double-transgenic progeny of these mice that also express human β-synuclein, a homologue of α-synuclein, show significant amelioration of all three phenotypes. We demonstrate here that β- and γ-synuclein (a third homologue that is expressed primarily in peripheral neurons) are natively unfolded in monomeric form, but structured in protofibrillar form. β-Synuclein protofibrils do not bind to or permeabilize synthetic vesicles, unlike protofibrils comprising α-synuclein or γ-synuclein. Significantly, β-synuclein inhibits the generation of A53T α-synuclein protofibrils and fibrils. This finding provides a rationale for the phenotype of the double-transgenic mice and suggests a therapeutic strategy for PD.