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Loss of the Parkinson's disease-linked gene DJ-1 perturbs mitochondrial dynamics.
Hum Mol Genet. 2010 Oct 01; 19(19):3734-46.HM

Abstract

Growing evidence highlights a role for mitochondrial dysfunction and oxidative stress as underlying contributors to Parkinson's disease (PD) pathogenesis. DJ-1 (PARK7) is a recently identified recessive familial PD gene. Its loss leads to increased susceptibility of neurons to oxidative stress and death. However, its mechanism of action is not fully understood. Presently, we report that DJ-1 deficiency in cell lines, cultured neurons, mouse brain and lymphoblast cells derived from DJ-1 patients display aberrant mitochondrial morphology. We also show that these DJ-1-dependent mitochondrial defects contribute to oxidative stress-induced sensitivity to cell death since reversal of this fragmented mitochondrial phenotype abrogates neuronal cell death. Reactive oxygen species (ROS) appear to play a critical role in the observed defects, as ROS scavengers rescue the phenotype and mitochondria isolated from DJ-1 deficient animals produce more ROS compared with control. Importantly, the aberrant mitochondrial phenotype can be rescued by the expression of Pink1 and Parkin, two PD-linked genes involved in regulating mitochondrial dynamics and quality control. Finally, we show that DJ-1 deficiency leads to altered autophagy in murine and human cells. Our findings define a mechanism by which the DJ-1-dependent mitochondrial defects contribute to the increased sensitivity to oxidative stress-induced cell death that has been previously reported.

Authors+Show Affiliations

Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20639397

Citation

Irrcher, I, et al. "Loss of the Parkinson's Disease-linked Gene DJ-1 Perturbs Mitochondrial Dynamics." Human Molecular Genetics, vol. 19, no. 19, 2010, pp. 3734-46.
Irrcher I, Aleyasin H, Seifert EL, et al. Loss of the Parkinson's disease-linked gene DJ-1 perturbs mitochondrial dynamics. Hum Mol Genet. 2010;19(19):3734-46.
Irrcher, I., Aleyasin, H., Seifert, E. L., Hewitt, S. J., Chhabra, S., Phillips, M., Lutz, A. K., Rousseaux, M. W., Bevilacqua, L., Jahani-Asl, A., Callaghan, S., MacLaurin, J. G., Winklhofer, K. F., Rizzu, P., Rippstein, P., Kim, R. H., Chen, C. X., Fon, E. A., Slack, R. S., ... Park, D. S. (2010). Loss of the Parkinson's disease-linked gene DJ-1 perturbs mitochondrial dynamics. Human Molecular Genetics, 19(19), 3734-46. https://doi.org/10.1093/hmg/ddq288
Irrcher I, et al. Loss of the Parkinson's Disease-linked Gene DJ-1 Perturbs Mitochondrial Dynamics. Hum Mol Genet. 2010 Oct 1;19(19):3734-46. PubMed PMID: 20639397.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Loss of the Parkinson's disease-linked gene DJ-1 perturbs mitochondrial dynamics. AU - Irrcher,I, AU - Aleyasin,H, AU - Seifert,E L, AU - Hewitt,S J, AU - Chhabra,S, AU - Phillips,M, AU - Lutz,A K, AU - Rousseaux,M W C, AU - Bevilacqua,L, AU - Jahani-Asl,A, AU - Callaghan,S, AU - MacLaurin,J G, AU - Winklhofer,K F, AU - Rizzu,P, AU - Rippstein,P, AU - Kim,R H, AU - Chen,C X, AU - Fon,E A, AU - Slack,R S, AU - Harper,M E, AU - McBride,H M, AU - Mak,T W, AU - Park,D S, Y1 - 2010/07/16/ PY - 2010/7/20/entrez PY - 2010/7/20/pubmed PY - 2011/1/5/medline SP - 3734 EP - 46 JF - Human molecular genetics JO - Hum Mol Genet VL - 19 IS - 19 N2 - Growing evidence highlights a role for mitochondrial dysfunction and oxidative stress as underlying contributors to Parkinson's disease (PD) pathogenesis. DJ-1 (PARK7) is a recently identified recessive familial PD gene. Its loss leads to increased susceptibility of neurons to oxidative stress and death. However, its mechanism of action is not fully understood. Presently, we report that DJ-1 deficiency in cell lines, cultured neurons, mouse brain and lymphoblast cells derived from DJ-1 patients display aberrant mitochondrial morphology. We also show that these DJ-1-dependent mitochondrial defects contribute to oxidative stress-induced sensitivity to cell death since reversal of this fragmented mitochondrial phenotype abrogates neuronal cell death. Reactive oxygen species (ROS) appear to play a critical role in the observed defects, as ROS scavengers rescue the phenotype and mitochondria isolated from DJ-1 deficient animals produce more ROS compared with control. Importantly, the aberrant mitochondrial phenotype can be rescued by the expression of Pink1 and Parkin, two PD-linked genes involved in regulating mitochondrial dynamics and quality control. Finally, we show that DJ-1 deficiency leads to altered autophagy in murine and human cells. Our findings define a mechanism by which the DJ-1-dependent mitochondrial defects contribute to the increased sensitivity to oxidative stress-induced cell death that has been previously reported. SN - 1460-2083 UR - https://www.unboundmedicine.com/medline/citation/20639397/Loss_of_the_Parkinson's_disease_linked_gene_DJ_1_perturbs_mitochondrial_dynamics_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddq288 DB - PRIME DP - Unbound Medicine ER -