The A53T α-synuclein mutation increases iron-dependent aggregation and toxicity

Natalie Ostrerova-Golts, Leonard Petrucelli, John Hardy, John M. Lee, Matthew Farer, Benjamin Wolozin

Research output: Contribution to journalArticle

390 Scopus citations

Abstract

Parkinson's disease (PD) is the most common motor disorder affecting the elderly. PD is characterized by the formation of Lewy bodies and death of dopaminergic neurons. The mechanisms underlying PD are unknown, but the discoveries that mutations in α-synuclein can cause familial PD and that α-synuclein accumulates in Lewy bodies suggest that α-synuclein participates in the pathophysiology of PD. Using human BE-M17 neuroblastoma cells overexpressing wild-type, A53T, or A30P α-synuclein, we now show that iron and free radical generators, such as dopamine or hydrogen peroxide, stimulate the production of intracellular aggregates that contain α-synuclein and ubiquitin. The aggregates can be identified by immunocytochemistry, electron microscopy, or the histochemical stain thioflavine S. The amount of aggregation occurring in the cells is dependent on the amount of α-synuclein expressed and the type of α-synuclein expressed, with the amount of α-synuclein aggregation following a rank order of A53T > A30P > wild-type > untransfected. In addition to stimulating aggregate formation, α-synuclein also appears to induce toxicity. BE-M17 neuroblastoma cells overexpressing α-synuclein show up to a fourfold increase in vulnerability to toxicity induced by iron. The vulnerability follows the same rank order as for aggregation. These data raise the possibility that α-synuclein acts in concert with iron and dopamine to induce formation of Lewy body pathology in PD and cell death in PD.

Original languageEnglish (US)
Pages (from-to)6048-6054
Number of pages7
JournalJournal of Neuroscience
Volume20
Issue number16
DOIs
StatePublished - Aug 15 2000

Keywords

  • Dopamine
  • Lewy body
  • Neurodegeneration
  • Oxidation
  • Parkinson's disease
  • Ubiquitin

ASJC Scopus subject areas

  • Neuroscience(all)

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