Characterization of hydrophobic residue requirements for α-synuclein fibrillization

Elisa A. Waxman, Joseph R. Mazzulli, Benoit I. Giasson

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

α-Synuclein is the major component of pathological inclusions characteristic of diseases like Parkinson's disease, dementia with Lewy bodies, and multiple-system atrophy. A role for α-synuclein in neurodegenerative diseases is further supported by point mutations and duplication and triplication of the α-synuclein gene (SNCA) that are causative of these disorders. The middle hydrophobic region of the α-synuclein protein, also termed the "non-Aβ component of Alzheimer's disease amyloid plaque (NAC)" domain, is required for α-synuclein to polymerize into amyloid filaments, which are the major components of α-synuclein pathological inclusions. In this study, we assessed the importance of specific stretches of hydrophobic residues in driving the intrinsic ability of α-synuclein to polymerize. Several small deletions, even one with as few as two amino acid residues (A76 and V77), dramatically impaired the ability of α-synuclein to polymerize into mature amyloidogenic fibrils, and instead, it preferentially formed oligomers. However, this inhibition of filament assembly was clearly dependent on the spatial context, since similar and larger hydrophobic deletions in other parts of the NAC domain reduced only the rate of fibril formation, without abrogating filament assembly. Further, mutation of residue E83 to an A rescued the ability of mutant Δ76-77 α-synuclein to polymerize. These findings support the notion that while both the location and hydrophobicity of protein segments are important elements that affect the propensity to form amyloid fibrils, the intrinsic ability of a polypeptide to fold structurally into amyloid is also critical.

Original languageEnglish (US)
Pages (from-to)9427-9436
Number of pages10
JournalBiochemistry
Volume48
Issue number40
DOIs
StatePublished - Oct 22 2009

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Synucleins
Aptitude
Amyloid
Neurodegenerative diseases
Multiple System Atrophy
Lewy Body Disease
Amyloid Plaques
Cytomegalovirus Infections
Hydrophobicity
Hydrophobic and Hydrophilic Interactions
Point Mutation
Oligomers
Neurodegenerative Diseases
Parkinson Disease
Alzheimer Disease
Proteins
Genes

ASJC Scopus subject areas

  • Biochemistry

Cite this

Waxman, Elisa A. ; Mazzulli, Joseph R. ; Giasson, Benoit I. / Characterization of hydrophobic residue requirements for α-synuclein fibrillization. In: Biochemistry. 2009 ; Vol. 48, No. 40. pp. 9427-9436.
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Characterization of hydrophobic residue requirements for α-synuclein fibrillization. / Waxman, Elisa A.; Mazzulli, Joseph R.; Giasson, Benoit I.

In: Biochemistry, Vol. 48, No. 40, 22.10.2009, p. 9427-9436.

Research output: Contribution to journalArticle

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