Abstract：
:Two mutations in the alpha-synuclein gene (A30P and A53T) have been linked to autosomal dominant early-onset Parkinson's disease (PD). Both mutations promote the formation of transient protofibrils (prefibrillar oligomers), suggesting that protofibrils are linked to cytotoxicity. In this work, the effect of these mutations on the structure of alpha-synuclein oligomers was investigated using electron microscopy and digital image processing. The PD-linked mutations (A30P and A53T) were observed to affect both the morphology and the size distribution of alpha-synuclein protofibrils (measured by analytical ultracentrifugation and scanning transmission electron microscopy). The A30P variant was observed to promote the formation of annular, pore-like protofibrils, whereas A53T promotes formation of annular and tubular protofibrillar structures. Wild-type alpha-synuclein also formed annular protofibrils, but only after extended incubation. The formation of pore-like oligomeric structures may explain the membrane permeabilization activity of alpha-synuclein protofibrils. These structures may contribute to the pathogenesis of PD.
journal_name
J Mol Bioljournal_title
Journal of molecular biologyauthors
Lashuel HA,Petre BM,Wall J,Simon M,Nowak RJ,Walz T,Lansbury PT Jrdoi
10.1016/s0022-2836(02)00735-0keywords:
subject
Has Abstractpub_date
2002-10-04 00:00:00pages
1089-102issue
5eissn
0022-2836issn
1089-8638pii
S0022283602007350journal_volume
322pub_type
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