Systematic Comparison of the Effects of Alpha-synuclein Mutations on Its Oligomerization and Aggregation

Diana F. Lázaro, Eva F. Rodrigues, Ramona Langohr, Hedieh Shahpasandzadeh, Thales Ribeiro, Patrícia Guerreiro, Ellen Gerhardt, Katharina Kröhnert, Jochen Klucken, Marcos D. Pereira, Blagovesta Popova, Niels Kruse, Brit Mollenhauer, Silvio O. Rizzoli, Gerhard H. Braus, Karin M. Danzer, Tiago F. Outeiro*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

137 Citations (Scopus)

Abstract

Aggregation of alpha-synuclein (ASYN) in Lewy bodies and Lewy neurites is the typical pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Furthermore, mutations in the gene encoding for ASYN are associated with familial and sporadic forms of PD, suggesting this protein plays a central role in the disease. However, the precise contribution of ASYN to neuronal dysfunction and death is unclear. There is intense debate about the nature of the toxic species of ASYN and little is known about the molecular determinants of oligomerization and aggregation of ASYN in the cell. In order to clarify the effects of different mutations on the propensity of ASYN to oligomerize and aggregate, we assembled a panel of 19 ASYN variants and compared their behaviour. We found that familial mutants linked to PD (A30P, E46K, H50Q, G51D and A53T) exhibited identical propensities to oligomerize in living cells, but had distinct abilities to form inclusions. While the A30P mutant reduced the percentage of cells with inclusions, the E46K mutant had the opposite effect. Interestingly, artificial proline mutants designed to interfere with the helical structure of the N-terminal domain, showed increased propensity to form oligomeric species rather than inclusions. Moreover, lysine substitution mutants increased oligomerization and altered the pattern of aggregation. Altogether, our data shed light into the molecular effects of ASYN mutations in a cellular context, and established a common ground for the study of genetic and pharmacological modulators of the aggregation process, opening new perspectives for therapeutic intervention in PD and other synucleinopathies.

Original languageEnglish
JournalPLoS Genetics
Volume10
Issue number11
DOIs
Publication statusPublished - 1 Nov 2014
Externally publishedYes

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