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

378 Citations (Scopus)

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
StatePublished - Aug 15 2000
Externally publishedYes

Fingerprint

Synucleins
Iron
Mutation
Parkinson Disease
Lewy Bodies
Neuroblastoma
Dopamine
Dopaminergic Neurons
Ubiquitin
Hydrogen Peroxide
Free Radicals

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Ostrerova-Golts, N., Petrucelli, L., Hardy, J., Lee, J. M., Farer, M., & Wolozin, B. (2000). The A53T α-synuclein mutation increases iron-dependent aggregation and toxicity. Journal of Neuroscience, 20(16), 6048-6054.

The A53T α-synuclein mutation increases iron-dependent aggregation and toxicity. / Ostrerova-Golts, Natalie; Petrucelli, Leonard; Hardy, John; Lee, John M.; Farer, Matthew; Wolozin, Benjamin.

In: Journal of Neuroscience, Vol. 20, No. 16, 15.08.2000, p. 6048-6054.

Research output: Contribution to journalArticle

Ostrerova-Golts, N, Petrucelli, L, Hardy, J, Lee, JM, Farer, M & Wolozin, B 2000, 'The A53T α-synuclein mutation increases iron-dependent aggregation and toxicity', Journal of Neuroscience, vol. 20, no. 16, pp. 6048-6054.
Ostrerova-Golts N, Petrucelli L, Hardy J, Lee JM, Farer M, Wolozin B. The A53T α-synuclein mutation increases iron-dependent aggregation and toxicity. Journal of Neuroscience. 2000 Aug 15;20(16):6048-6054.
Ostrerova-Golts, Natalie ; Petrucelli, Leonard ; Hardy, John ; Lee, John M. ; Farer, Matthew ; Wolozin, Benjamin. / The A53T α-synuclein mutation increases iron-dependent aggregation and toxicity. In: Journal of Neuroscience. 2000 ; Vol. 20, No. 16. pp. 6048-6054.
@article{6792b4d2347348548e7984300d3fdf8e,
title = "The A53T α-synuclein mutation increases iron-dependent aggregation and toxicity",
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.",
keywords = "Dopamine, Lewy body, Neurodegeneration, Oxidation, Parkinson's disease, Ubiquitin",
author = "Natalie Ostrerova-Golts and Leonard Petrucelli and John Hardy and Lee, {John M.} and Matthew Farer and Benjamin Wolozin",
year = "2000",
month = "8",
day = "15",
language = "English (US)",
volume = "20",
pages = "6048--6054",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "16",

}

TY - JOUR

T1 - The A53T α-synuclein mutation increases iron-dependent aggregation and toxicity

AU - Ostrerova-Golts, Natalie

AU - Petrucelli, Leonard

AU - Hardy, John

AU - Lee, John M.

AU - Farer, Matthew

AU - Wolozin, Benjamin

PY - 2000/8/15

Y1 - 2000/8/15

N2 - 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.

AB - 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.

KW - Dopamine

KW - Lewy body

KW - Neurodegeneration

KW - Oxidation

KW - Parkinson's disease

KW - Ubiquitin

UR - http://www.scopus.com/inward/record.url?scp=0034663039&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034663039&partnerID=8YFLogxK

M3 - Article

C2 - 10934254

AN - SCOPUS:0034663039

VL - 20

SP - 6048

EP - 6054

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 16

ER -