Role of protein-water interactions and electrostatics in alpha-synuclein fibril formation.

Abstract:

:Deposition of misfolded alpha-synuclein is a critical factor in several neurodegenerative disorders. Filamentous alpha-synuclein is the major component of Lewy bodies and Lewy neurites, the intracellular inclusions in the dopaminergic neurons of the substantia nigra, which are considered the pathological hallmark of Parkinson's disease. We show here that anions induce partial folding of alpha-synuclein at neutral pH, forming a critical amyloidogenic intermediate, which leads to significant acceleration of the rate of fibrillation. The magnitude of the accelerating effect generally followed the position of the anions in the Hofmeister series, indicating a major role of protein-water-anion interactions in the process at salt concentrations above 10 mM. Below this concentration, electrostatic effects dominated in the mechanism of anion-induced fibrillation. The acceleration of fibrillation by anions was also dependent on the cation. Moderate concentrations of anions affected both the rates of nucleation and the elongation of alpha-synuclein fibrillation, primarily via their effect on the interaction of the protein with water.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Munishkina LA,Henriques J,Uversky VN,Fink AL

doi

10.1021/bi034938r

subject

Has Abstract

pub_date

2004-03-23 00:00:00

pages

3289-300

issue

11

eissn

0006-2960

issn

1520-4995

journal_volume

43

pub_type

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