Nature Medicine
4, 1318 - 1320 (1998)
doi:10.1038/3311
Accelerated in vitro fibril formation by a mutant  -synuclein
linked to early-onset Parkinson diseaseKelly A. Conway, James D. Harper
& Peter T. Lansbury
Center for Neurologic Diseases, Brigham and Women's
Hospital and Department of Neurology, Harvard Medical School, Harvard Institutes
of Medicine, 77 Ave Louis Pasteur, Boston,
Massachusetts 02115, USA
Correspondence should be addressed to lansbury@cnd.bwh.harvard.eduTwo mutations in the gene encoding  -synuclein have been linked to
early-onset Parkinson's disease1,
2,
3 (PD). -Synuclein
is a component of Lewy bodies, the fibrous cytoplasmic inclusions characteristic
of nigral dopaminergic neurons in the PD brain4. This connection
between genetics and pathology suggests that the -synuclein mutations
may promote PD pathogenesis by accelerating Lewy body formation. To test this,
we studied -synuclein folding and aggregation in vitro, in the
absence of other Lewy body-associated molecules. We demonstrate here that
both mutant forms of -synuclein (A53T and A30P) are, like wild-type -synuclein5 (WT), disordered in dilute solution. However, at higher concentrations,
Lewy body-like fibrils and discrete spherical assemblies are formed; most
rapidly by A53T. Thus, mutation-induced acceleration of -synuclein
fibril formation may contribute to the early onset of familial PD.
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