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

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The accumulation of aggregated proteins in the brain is common across several neurodegenerative disorders. In Parkinson's disease (PD), the protein alpha-synuclein (ASYN) is the major component of aggregates known as Lewy bodies. It is currently unclear whether protein aggregates are protective or detrimental for neuronal function and survival. The present hypothesis is that smaller aggregated species, known as oligomers, might constitute the toxic forms of ASYN. Several mutations in ASYN cause familial forms of PD. In the laboratory, artificial mutations have been designed to enable the study of the aggregation process. However, different studies relied on the use of different model systems, compromising the interpretation of the effects of the mutations. Here, we addressed this by (i) assembling a panel of 19 ASYN variants and (ii) by performing a systematic comparison of the effects of the mutations in mammalian cell models. Interestingly, our study enabled us to correlate oligomerization and aggregation of ASYN in cells. Altogether, our data shed light into the molecular determinants of ASYN aggregation, opening novel avenues for the identification of modulators of ASYN aggregation, which conceal great hopes towards the development of strategies for therapeutic intervention in PD and other synucleinopathies.

Vyšlo v časopise: Systematic Comparison of the Effects of Alpha-synuclein Mutations on Its Oligomerization and Aggregation. PLoS Genet 10(11): e32767. doi:10.1371/journal.pgen.1004741
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004741

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