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

63 Citations (Scopus)

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

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Synucleins
Transgenic Mice
Neurons
Endopeptidase K
Nerve Degeneration
Intrinsic Factor
Poisons
Neurodegenerative Diseases
Detergents
Nervous System
Urea
Digestion
Hot Temperature
Antibodies
Brain
In Vitro Techniques

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Tsika, Elpida ; Moysidou, Maria ; Guo, Jing ; Cushman, Mimi ; Gannon, Patrick ; Sandaltzopoulos, Raphael ; Giasson, Benoit I. ; Krainc, Dimitri ; Ischiropoulos, Harry ; Mazzulli, Joseph R. / Distinct region-specific α-synuclein oligomers in A53T transgenic mice : Implications for neurodegeneration. In: Journal of Neuroscience. 2010 ; Vol. 30, No. 9. pp. 3409-3418.
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author = "Elpida Tsika and Maria Moysidou and Jing Guo and Mimi Cushman and Patrick Gannon and Raphael Sandaltzopoulos and Giasson, {Benoit I.} and Dimitri Krainc and Harry Ischiropoulos and Mazzulli, {Joseph R.}",
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Tsika, E, Moysidou, M, Guo, J, Cushman, M, Gannon, P, Sandaltzopoulos, R, Giasson, BI, Krainc, D, Ischiropoulos, H & Mazzulli, JR 2010, 'Distinct region-specific α-synuclein oligomers in A53T transgenic mice: Implications for neurodegeneration', Journal of Neuroscience, vol. 30, no. 9, pp. 3409-3418. https://doi.org/10.1523/JNEUROSCI.4977-09.2010

Distinct region-specific α-synuclein oligomers in A53T transgenic mice : Implications for neurodegeneration. / Tsika, Elpida; Moysidou, Maria; Guo, Jing; Cushman, Mimi; Gannon, Patrick; Sandaltzopoulos, Raphael; Giasson, Benoit I.; Krainc, Dimitri; Ischiropoulos, Harry; Mazzulli, Joseph R.

In: Journal of Neuroscience, Vol. 30, No. 9, 03.03.2010, p. 3409-3418.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Distinct region-specific α-synuclein oligomers in A53T transgenic mice

T2 - Implications for neurodegeneration

AU - Tsika, Elpida

AU - Moysidou, Maria

AU - Guo, Jing

AU - Cushman, Mimi

AU - Gannon, Patrick

AU - Sandaltzopoulos, Raphael

AU - Giasson, Benoit I.

AU - Krainc, Dimitri

AU - Ischiropoulos, Harry

AU - Mazzulli, Joseph R.

PY - 2010/3/3

Y1 - 2010/3/3

N2 - 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.

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