DJ-1 interactions with α-synuclein attenuate aggregation and cellular toxicity in models of Parkinson's disease

L Zondler, L Miller-Fleming, M Repici, S Gonçalves, S Tenreiro, R Rosado-Ramos, C Betzer, K R Straatman, P H Jensen, F Giorgini, T F Outeiro

Research output: Contribution to journalArticle

Abstract

Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by the loss of neurons in the substantia nigra pars compacta and the presence of Lewy bodies in surviving neurons. These intracellular protein inclusions are primarily composed of misfolded α-synuclein (aSyn), which has also been genetically linked to familial and sporadic forms of PD. DJ-1 is a small ubiquitously expressed protein implicated in several pathways associated with PD pathogenesis. Although mutations in the gene encoding DJ-1 lead to familial early-onset PD, the exact mechanisms responsible for its role in PD pathogenesis are still elusive. Previous work has found that DJ-1--which has protein chaperone-like activity--modulates aSyn aggregation. Here, we investigated possible physical interactions between aSyn and DJ-1 and any consequent functional and pathological relevance. We found that DJ-1 interacts directly with aSyn monomers and oligomers in vitro, and that this also occurs in living cells. Notably, several PD-causing mutations in DJ-1 constrain this interaction. In addition, we found that overexpression of DJ-1 reduces aSyn dimerization, whereas mutant forms of DJ-1 impair this process. Finally, we found that human DJ-1 as well as yeast orthologs of DJ-1 reversed aSyn-dependent cellular toxicity in Saccharomyces cerevisiae. Taken together, these data suggest that direct interactions between DJ-1 and aSyn constitute the basis for a neuroprotective mechanism and that familial mutations in DJ-1 may contribute to PD by disrupting these interactions.

Original languageEnglish
Article numbere1350
JournalCell Death and Disease
Volume5
DOIs
Publication statusPublished - 24 Jul 2014

Fingerprint

Synucleins
Parkinson Disease
Mutation
Lewy Bodies
Neurons
Proteins
Dimerization
Neurodegenerative Diseases
Saccharomyces cerevisiae
Yeasts

Bibliographical note

Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 3.0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/

Keywords

  • Animals
  • Brain/metabolism
  • Cell Line
  • Humans
  • Intracellular Signaling Peptides and Proteins/genetics
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Oncogene Proteins/genetics
  • Parkinson Disease/genetics
  • Peroxiredoxins/genetics
  • Protein Aggregates
  • Protein Binding
  • Protein Deglycase DJ-1
  • alpha-Synuclein/chemistry

Cite this

Zondler, L., Miller-Fleming, L., Repici, M., Gonçalves, S., Tenreiro, S., Rosado-Ramos, R., ... Outeiro, T. F. (2014). DJ-1 interactions with α-synuclein attenuate aggregation and cellular toxicity in models of Parkinson's disease. Cell Death and Disease, 5, [e1350]. https://doi.org/10.1038/cddis.2014.307
Zondler, L ; Miller-Fleming, L ; Repici, M ; Gonçalves, S ; Tenreiro, S ; Rosado-Ramos, R ; Betzer, C ; Straatman, K R ; Jensen, P H ; Giorgini, F ; Outeiro, T F. / DJ-1 interactions with α-synuclein attenuate aggregation and cellular toxicity in models of Parkinson's disease. In: Cell Death and Disease. 2014 ; Vol. 5.
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Zondler, L, Miller-Fleming, L, Repici, M, Gonçalves, S, Tenreiro, S, Rosado-Ramos, R, Betzer, C, Straatman, KR, Jensen, PH, Giorgini, F & Outeiro, TF 2014, 'DJ-1 interactions with α-synuclein attenuate aggregation and cellular toxicity in models of Parkinson's disease', Cell Death and Disease, vol. 5, e1350. https://doi.org/10.1038/cddis.2014.307

DJ-1 interactions with α-synuclein attenuate aggregation and cellular toxicity in models of Parkinson's disease. / Zondler, L; Miller-Fleming, L; Repici, M; Gonçalves, S; Tenreiro, S; Rosado-Ramos, R; Betzer, C; Straatman, K R; Jensen, P H; Giorgini, F; Outeiro, T F.

In: Cell Death and Disease, Vol. 5, e1350, 24.07.2014.

Research output: Contribution to journalArticle

TY - JOUR

T1 - DJ-1 interactions with α-synuclein attenuate aggregation and cellular toxicity in models of Parkinson's disease

AU - Zondler, L

AU - Miller-Fleming, L

AU - Repici, M

AU - Gonçalves, S

AU - Tenreiro, S

AU - Rosado-Ramos, R

AU - Betzer, C

AU - Straatman, K R

AU - Jensen, P H

AU - Giorgini, F

AU - Outeiro, T F

N1 - Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 3.0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/

PY - 2014/7/24

Y1 - 2014/7/24

N2 - Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by the loss of neurons in the substantia nigra pars compacta and the presence of Lewy bodies in surviving neurons. These intracellular protein inclusions are primarily composed of misfolded α-synuclein (aSyn), which has also been genetically linked to familial and sporadic forms of PD. DJ-1 is a small ubiquitously expressed protein implicated in several pathways associated with PD pathogenesis. Although mutations in the gene encoding DJ-1 lead to familial early-onset PD, the exact mechanisms responsible for its role in PD pathogenesis are still elusive. Previous work has found that DJ-1--which has protein chaperone-like activity--modulates aSyn aggregation. Here, we investigated possible physical interactions between aSyn and DJ-1 and any consequent functional and pathological relevance. We found that DJ-1 interacts directly with aSyn monomers and oligomers in vitro, and that this also occurs in living cells. Notably, several PD-causing mutations in DJ-1 constrain this interaction. In addition, we found that overexpression of DJ-1 reduces aSyn dimerization, whereas mutant forms of DJ-1 impair this process. Finally, we found that human DJ-1 as well as yeast orthologs of DJ-1 reversed aSyn-dependent cellular toxicity in Saccharomyces cerevisiae. Taken together, these data suggest that direct interactions between DJ-1 and aSyn constitute the basis for a neuroprotective mechanism and that familial mutations in DJ-1 may contribute to PD by disrupting these interactions.

AB - Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by the loss of neurons in the substantia nigra pars compacta and the presence of Lewy bodies in surviving neurons. These intracellular protein inclusions are primarily composed of misfolded α-synuclein (aSyn), which has also been genetically linked to familial and sporadic forms of PD. DJ-1 is a small ubiquitously expressed protein implicated in several pathways associated with PD pathogenesis. Although mutations in the gene encoding DJ-1 lead to familial early-onset PD, the exact mechanisms responsible for its role in PD pathogenesis are still elusive. Previous work has found that DJ-1--which has protein chaperone-like activity--modulates aSyn aggregation. Here, we investigated possible physical interactions between aSyn and DJ-1 and any consequent functional and pathological relevance. We found that DJ-1 interacts directly with aSyn monomers and oligomers in vitro, and that this also occurs in living cells. Notably, several PD-causing mutations in DJ-1 constrain this interaction. In addition, we found that overexpression of DJ-1 reduces aSyn dimerization, whereas mutant forms of DJ-1 impair this process. Finally, we found that human DJ-1 as well as yeast orthologs of DJ-1 reversed aSyn-dependent cellular toxicity in Saccharomyces cerevisiae. Taken together, these data suggest that direct interactions between DJ-1 and aSyn constitute the basis for a neuroprotective mechanism and that familial mutations in DJ-1 may contribute to PD by disrupting these interactions.

KW - Animals

KW - Brain/metabolism

KW - Cell Line

KW - Humans

KW - Intracellular Signaling Peptides and Proteins/genetics

KW - Mice

KW - Mice, Inbred C57BL

KW - Mutation

KW - Oncogene Proteins/genetics

KW - Parkinson Disease/genetics

KW - Peroxiredoxins/genetics

KW - Protein Aggregates

KW - Protein Binding

KW - Protein Deglycase DJ-1

KW - alpha-Synuclein/chemistry

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U2 - 10.1038/cddis.2014.307

DO - 10.1038/cddis.2014.307

M3 - Article

C2 - 25058424

VL - 5

JO - Cell Death and Disease

JF - Cell Death and Disease

SN - 2041-4889

M1 - e1350

ER -