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 language | English |
|---|---|
| Article number | e1884 |
| Journal | PLoS One |
| Volume | 3 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Apr 2 2008 |
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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 journal › Article
}
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 -