DJ-1 modulates α-synuclein aggregation state in a cellular model of oxidative stress: Relevance for Parkinson's Disease and involvement of HSP70

Sara Batelli, Diego Albani, Raffaela Rametta, Letizia Polito, Francesca Prato, Marzia Pesaresi, Alessandro Negro, Gianluigi Forloni

Research output: Contribution to journalArticle

98 Citations (Scopus)

Abstract

Background: Parkinson's disease (PD) is a neurodegeneration pathology wose molecular etiopathogenesis is not known. Novel contributions have come from familial forms of PD caused by alterations in genes with apparently unrelated physiological functions. The gene coding for alpha-synuclein (α-syn) (PARK1) has been investigated as α-syn is located in Lewy bodies (LB), intraneuronal inclusions in the substantia nigra (SN) of PD patients. A-syn has neuroprotective chaperone-like and antioxidant functions and is involved in dopamine storage and release, DJ-1 (PARK7), another family-PD-linked gene causing an autosomal recessive form of the pathology, shows antioxidant and chaperone-like activities too. Methodology/Principal Findings: The present study addressed the question whether α-syn and DJ-1 interact functionally, with a view to findings some mechanism linking DJ-1 inactivation and α-syn aggregation and toxicity. We developed an in vitro model of α-syn toxicity in the human neuroblastoma cell line SK-N-BE, influencing DJ-1 and α-syn intracellular concentrations by exogenous addition of the fusion proteins TAT-α-syn and TAT-DJ-1; DJ-1 was inactivated by the siRNA method. On a micromolar scale TAT-α-syn aggregated and triggered neurotoxicity, while on the nanomolar scale it was neuroprotective against oxidative stress (induces by H2O2 or 6-hydroxydopamine). TAT-DJ-1 increased the expression of HSP70, while DJ-1 silencing made SK-N-BE cells more susceptible to oxidative challenge, rendering TAT-α-syn neurotoxic at nanomolar scale, with the appearance of TAT-α-syn aggregates. Conclusion/Significance: DJ-1 inactivation may thus promote α-syn aggregation and the related toxicity, and in this model HSP70 is involved in the antioxidant response and in the regulation of α-syn fibril formation.

Original languageEnglish
Article numbere1884
JournalPLoS One
Volume3
Issue number4
DOIs
Publication statusPublished - Apr 2 2008

Fingerprint

Synucleins
Oxidative stress
Parkinson disease
Parkinson Disease
Oxidative Stress
oxidative stress
Agglomeration
Toxicity
Antioxidants
Genes
Pathology
toxicity
antioxidants
inactivation
Lewy Bodies
alpha-Synuclein
neurotoxicity
human cell lines
genes
Molecular Pathology

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

DJ-1 modulates α-synuclein aggregation state in a cellular model of oxidative stress : Relevance for Parkinson's Disease and involvement of HSP70. / Batelli, Sara; Albani, Diego; Rametta, Raffaela; Polito, Letizia; Prato, Francesca; Pesaresi, Marzia; Negro, Alessandro; Forloni, Gianluigi.

In: PLoS One, Vol. 3, No. 4, e1884, 02.04.2008.

Research output: Contribution to journalArticle

@article{6627aa9f0e624231b7250b8ef08545b5,
title = "DJ-1 modulates α-synuclein aggregation state in a cellular model of oxidative stress: Relevance for Parkinson's Disease and involvement of HSP70",
abstract = "Background: Parkinson's disease (PD) is a neurodegeneration pathology wose molecular etiopathogenesis is not known. Novel contributions have come from familial forms of PD caused by alterations in genes with apparently unrelated physiological functions. The gene coding for alpha-synuclein (α-syn) (PARK1) has been investigated as α-syn is located in Lewy bodies (LB), intraneuronal inclusions in the substantia nigra (SN) of PD patients. A-syn has neuroprotective chaperone-like and antioxidant functions and is involved in dopamine storage and release, DJ-1 (PARK7), another family-PD-linked gene causing an autosomal recessive form of the pathology, shows antioxidant and chaperone-like activities too. Methodology/Principal Findings: The present study addressed the question whether α-syn and DJ-1 interact functionally, with a view to findings some mechanism linking DJ-1 inactivation and α-syn aggregation and toxicity. We developed an in vitro model of α-syn toxicity in the human neuroblastoma cell line SK-N-BE, influencing DJ-1 and α-syn intracellular concentrations by exogenous addition of the fusion proteins TAT-α-syn and TAT-DJ-1; DJ-1 was inactivated by the siRNA method. On a micromolar scale TAT-α-syn aggregated and triggered neurotoxicity, while on the nanomolar scale it was neuroprotective against oxidative stress (induces by H2O2 or 6-hydroxydopamine). TAT-DJ-1 increased the expression of HSP70, while DJ-1 silencing made SK-N-BE cells more susceptible to oxidative challenge, rendering TAT-α-syn neurotoxic at nanomolar scale, with the appearance of TAT-α-syn aggregates. Conclusion/Significance: DJ-1 inactivation may thus promote α-syn aggregation and the related toxicity, and in this model HSP70 is involved in the antioxidant response and in the regulation of α-syn fibril formation.",
author = "Sara Batelli and Diego Albani and Raffaela Rametta and Letizia Polito and Francesca Prato and Marzia Pesaresi and Alessandro Negro and Gianluigi Forloni",
year = "2008",
month = "4",
day = "2",
doi = "10.1371/journal.pone.0001884",
language = "English",
volume = "3",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "4",

}

TY - JOUR

T1 - DJ-1 modulates α-synuclein aggregation state in a cellular model of oxidative stress

T2 - Relevance for Parkinson's Disease and involvement of HSP70

AU - Batelli, Sara

AU - Albani, Diego

AU - Rametta, Raffaela

AU - Polito, Letizia

AU - Prato, Francesca

AU - Pesaresi, Marzia

AU - Negro, Alessandro

AU - Forloni, Gianluigi

PY - 2008/4/2

Y1 - 2008/4/2

N2 - Background: Parkinson's disease (PD) is a neurodegeneration pathology wose molecular etiopathogenesis is not known. Novel contributions have come from familial forms of PD caused by alterations in genes with apparently unrelated physiological functions. The gene coding for alpha-synuclein (α-syn) (PARK1) has been investigated as α-syn is located in Lewy bodies (LB), intraneuronal inclusions in the substantia nigra (SN) of PD patients. A-syn has neuroprotective chaperone-like and antioxidant functions and is involved in dopamine storage and release, DJ-1 (PARK7), another family-PD-linked gene causing an autosomal recessive form of the pathology, shows antioxidant and chaperone-like activities too. Methodology/Principal Findings: The present study addressed the question whether α-syn and DJ-1 interact functionally, with a view to findings some mechanism linking DJ-1 inactivation and α-syn aggregation and toxicity. We developed an in vitro model of α-syn toxicity in the human neuroblastoma cell line SK-N-BE, influencing DJ-1 and α-syn intracellular concentrations by exogenous addition of the fusion proteins TAT-α-syn and TAT-DJ-1; DJ-1 was inactivated by the siRNA method. On a micromolar scale TAT-α-syn aggregated and triggered neurotoxicity, while on the nanomolar scale it was neuroprotective against oxidative stress (induces by H2O2 or 6-hydroxydopamine). TAT-DJ-1 increased the expression of HSP70, while DJ-1 silencing made SK-N-BE cells more susceptible to oxidative challenge, rendering TAT-α-syn neurotoxic at nanomolar scale, with the appearance of TAT-α-syn aggregates. Conclusion/Significance: DJ-1 inactivation may thus promote α-syn aggregation and the related toxicity, and in this model HSP70 is involved in the antioxidant response and in the regulation of α-syn fibril formation.

AB - Background: Parkinson's disease (PD) is a neurodegeneration pathology wose molecular etiopathogenesis is not known. Novel contributions have come from familial forms of PD caused by alterations in genes with apparently unrelated physiological functions. The gene coding for alpha-synuclein (α-syn) (PARK1) has been investigated as α-syn is located in Lewy bodies (LB), intraneuronal inclusions in the substantia nigra (SN) of PD patients. A-syn has neuroprotective chaperone-like and antioxidant functions and is involved in dopamine storage and release, DJ-1 (PARK7), another family-PD-linked gene causing an autosomal recessive form of the pathology, shows antioxidant and chaperone-like activities too. Methodology/Principal Findings: The present study addressed the question whether α-syn and DJ-1 interact functionally, with a view to findings some mechanism linking DJ-1 inactivation and α-syn aggregation and toxicity. We developed an in vitro model of α-syn toxicity in the human neuroblastoma cell line SK-N-BE, influencing DJ-1 and α-syn intracellular concentrations by exogenous addition of the fusion proteins TAT-α-syn and TAT-DJ-1; DJ-1 was inactivated by the siRNA method. On a micromolar scale TAT-α-syn aggregated and triggered neurotoxicity, while on the nanomolar scale it was neuroprotective against oxidative stress (induces by H2O2 or 6-hydroxydopamine). TAT-DJ-1 increased the expression of HSP70, while DJ-1 silencing made SK-N-BE cells more susceptible to oxidative challenge, rendering TAT-α-syn neurotoxic at nanomolar scale, with the appearance of TAT-α-syn aggregates. Conclusion/Significance: DJ-1 inactivation may thus promote α-syn aggregation and the related toxicity, and in this model HSP70 is involved in the antioxidant response and in the regulation of α-syn fibril formation.

UR - http://www.scopus.com/inward/record.url?scp=44849093321&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=44849093321&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0001884

DO - 10.1371/journal.pone.0001884

M3 - Article

C2 - 18382667

AN - SCOPUS:44849093321

VL - 3

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 4

M1 - e1884

ER -