Annular -Synuclein Protofibrils Are Produced When Spherical Protofibrils Are Incubated in Solution or Bound to Brain-Derived Membran
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- 作者：Tomas T. Ding ; Seung-Jae Lee ; Jean-Christophe Rochet ; and Peter T. Lansbury ; Jr.
- 刊名：Biochemistry
- 出版年：2002
- 出版时间：August 13, 2002
- 年：2002
- 卷：41
- 期：32
- 页码：10209 - 10217
- 全文大小：1079K
- 年卷期：v.41,no.32(August 13, 2002)
- ISSN：1520-4995
文摘
The Parkinson's disease substantia nigra is characterized by the loss of dopaminergic neuronsand the presence of cytoplasmic fibrillar Lewy bodies in surviving neurons. The major fibrillar protein ofLewy bodies is 
-synuclein. Two point mutations in the -synuclein gene are associated with autosomal-dominant Parkinson's disease (FPD). Studies of the in vitro fibrillization behavior of the mutant proteinssuggest that fibril precursors, or -synuclein protofibrils, rather than the fibrils, may be pathogenic. Atomicforce microscopy (AFM) revealed two distinct forms of protofibrillar -synuclein: rapidly formed sphericalprotofibrils and annular protofibrils, which were produced on prolonged incubation of spheres. The sphericalprotofibrils bound to brain-derived membrane fractions much more tightly than did monomeric or fibrillar-synuclein, and membrane-associated annular protofibrils were observed. The structural features of-synuclein annular protofibrils are reminiscent of bacterial pore-forming toxins and are consistent withtheir porelike activity in vitro. Thus, abnormal membrane permeabilization may be a pathogenic mechanismin PD.
-synuclein. Two point mutations in the -synuclein gene are associated with autosomal-dominant Parkinson's disease (FPD). Studies of the in vitro fibrillization behavior of the mutant proteinssuggest that fibril precursors, or -synuclein protofibrils, rather than the fibrils, may be pathogenic. Atomicforce microscopy (AFM) revealed two distinct forms of protofibrillar -synuclein: rapidly formed sphericalprotofibrils and annular protofibrils, which were produced on prolonged incubation of spheres. The sphericalprotofibrils bound to brain-derived membrane fractions much more tightly than did monomeric or fibrillar-synuclein, and membrane-associated annular protofibrils were observed. The structural features of-synuclein annular protofibrils are reminiscent of bacterial pore-forming toxins and are consistent withtheir porelike activity in vitro. Thus, abnormal membrane permeabilization may be a pathogenic mechanismin PD.