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

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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

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ASJC Scopus subject areas

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

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