Distinct region-specific α-synuclein oligomers in A53T transgenic mice: Implications for neurodegeneration

Elpida Tsika, Maria Moysidou, Jing Guo, Mimi Cushman, Patrick Gannon, Raphael Sandaltzopoulos, Benoit I. Giasson, Dimitri Krainc, Harry Ischiropoulos*, Joseph R. Mazzulli

*Corresponding author for this work

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

Aggregation of α-synuclein (α-syn), a process that generates oligomeric intermediates, is a common pathological feature of several neurodegenerative disorders. Despite the potential importance of the oligomeric α-syn intermediates in neuron function, their biochemical properties and pathobiological functions in vivo remain vastly unknown. Here we used two-dimensional analytical separation and an array of biochemical and cell-based assays to characterize α-syn oligomers that are present in the nervous system of A53T α-syn transgenic mice. The most prominent species identified were 53 Å detergent-soluble oligomers, which preceded neurological symptom onset, and were found at equivalent amounts in regions containing α-syn inclusions as well as histologically unaffected regions. These oligomers were resistant to SDS, heat, and urea but were sensitive to proteinase-K digestion. Although the oligomers shared similar basic biochemical properties, those obtained from inclusion-bearing regions were prominently reactive to antibodies that recognize oxidized α-syn oligomers, significantly accelerated aggregation of α-syn in vitro, and caused primary cortical neuron degeneration. In contrast, oligomers obtained from non-inclusion-bearing regions were not toxic and delayed the in vitro formation of α-syn fibrils. These data indicate that specific conformations of α-syn oligomers are present in distinct brain regions of A53T α-syn transgenic mice. The contribution of these oligomers to the development of neuron dysfunction appears to be independent of their absolute quantities and basic biochemical properties but is dictated by the composition and conformation of the intermediates as well as unrecognized brainregion-specific intrinsic factors.

Original languageEnglish (US)
Pages (from-to)3409-3418
Number of pages10
JournalJournal of Neuroscience
Volume30
Issue number9
DOIs
StatePublished - Mar 3 2010

ASJC Scopus subject areas

  • Neuroscience(all)

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    Tsika, E., Moysidou, M., Guo, J., Cushman, M., Gannon, P., Sandaltzopoulos, R., Giasson, B. I., Krainc, D., Ischiropoulos, H., & Mazzulli, J. R. (2010). Distinct region-specific α-synuclein oligomers in A53T transgenic mice: Implications for neurodegeneration. Journal of Neuroscience, 30(9), 3409-3418. https://doi.org/10.1523/JNEUROSCI.4977-09.2010