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PMID: 16239214 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Similar patterns of mitochondrial vulnerability and rescue induced by genetic modification of alpha-synuclein, parkin, and DJ-1 in Caenorhabditis elegans.

The Journal of biological chemistry ·Vol. 280 ·No. 52 ·2005-12-30 ·Pages 42655-42668

Ved R, Saha S, Westlund B, Perier C, Burnam L, Sluder A, Hoener M, Rodrigues CM, Alfonso A, Steer C, Liu L, Przedborski S, Wolozin B

Abstract

How genetic and environmental factors interact in Parkinson disease is poorly understood. We have now compared the patterns of vulnerability and rescue of Caenorhabditis elegans with genetic modifications of three different genetic factors implicated in Parkinson disease (PD). We observed that expressing alpha-synuclein, deleting parkin (K08E3.7), or knocking down DJ-1 (B0432.2) or parkin produces similar patterns of pharmacological vulnerability and rescue. C. elegans lines with these genetic changes were more vulnerable than nontransgenic nematodes to mitochondrial complex I inhibitors, including rotenone, fenperoximate, pyridaben, or stigmatellin. In contrast, the genetic manipulations did not increase sensitivity to paraquat, sodium azide, divalent metal ions (Fe(II) or Cu(II)), or etoposide compared with the nontransgenic nematodes. Each of the PD-related lines was also partially rescued by the antioxidant probucol, the mitochondrial complex II activator, D-beta-hydroxybutyrate, or the anti-apoptotic bile acid tauroursodeoxycholic acid. Complete protection in all lines was achieved by combining d-beta-hydroxybutyrate with tauroursodeoxycholic acid but not with probucol. These results show that diverse PD-related genetic modifications disrupt the mitochondrial function in C. elegans, and they raise the possibility that mitochondrial disruption is a pathway shared in common by many types of familial PD.

MeSH Terms
3-Hydroxybutyric Acid/pharmacology Amino Acid Sequence Animals Animals, Genetically Modified Antioxidants/pharmacology Apoptosis Benzoates/pharmacology Benzothiazoles Bile Acids and Salts/metabolism Caenorhabditis elegans/metabolism Cholagogues and Choleretics/pharmacology Copper/chemistry Disease Models, Animal Electron Transport Complex I/antagonists & inhibitors Gene Deletion Gene Expression Regulation Gene Library Genetic Techniques Humans Immunoblotting Intracellular Signaling Peptides and Proteins Ions Iron/chemistry Mitochondria/metabolism Molecular Sequence Data Mutagenesis Mutation Neurons/metabolism Oncogene Proteins/genetics Oxygen Consumption Paraquat/pharmacology Parkinson Disease/pathology Polyenes/pharmacology Probucol/pharmacology Protein Deglycase DJ-1 Pyrazoles/pharmacology Pyridazines/pharmacology RNA, Small Interfering/metabolism Rotenone/pharmacology Sequence Homology, Amino Acid Sodium Azide/pharmacology Taurochenodeoxycholic Acid/pharmacology Thiazoles/pharmacology Time Factors Transgenes Ubiquitin-Protein Ligases/genetics alpha-Synuclein/genetics
Chemicals
Antioxidants Benzoates Benzothiazoles Bile Acids and Salts Cholagogues and Choleretics Intracellular Signaling Peptides and Proteins Ions Oncogene Proteins Polyenes Pyrazoles Pyridazines RNA, Small Interfering Thiazoles alpha-Synuclein Rotenone thioflavin T pyridaben Taurochenodeoxycholic Acid ursodoxicoltaurine Copper stigmatellin Sodium Azide fenpyroximate Iron Ubiquitin-Protein Ligases parkin protein PARK7 protein, human Protein Deglycase DJ-1 Electron Transport Complex I Probucol Paraquat 3-Hydroxybutyric Acid
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Ved Rina
Deparment of Pharmacology, Boston University School of Medicine.
Saha Shamol
Deparment of Pharmacology, Boston University School of Medicine.
Westlund Beth
Deparment of Cambria Biosciences, Boston University School of Medicine.
Perier Celine
Hoffmann-La Roche, Columbia University.
Burnam Lucinda
Deparment of Cambria Biosciences, Boston University School of Medicine.
Sluder Anne
Deparment of Cambria Biosciences, Boston University School of Medicine.
Hoener Marius
Neurology Institute, Columbia University.
Rodrigues Cecilia Mp
Centro de Patogenese Molecular, Faculty of Pharmacy, University of Lisbon.
Alfonso Aixa
Dept. of Biological Science, University of Illinois.
Steer Clifford
Dept. of Medicine, University of Minnesota.
Liu Leo
Deparment of Cambria Biosciences, Boston University School of Medicine.
Przedborski Serge
Hoffmann-La Roche, Columbia University.
Wolozin Benjamin
Deparment of Pharmacology, Boston University School of Medicine.
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
0021-9258
DOI
10.1074/jbc.M505910200
Published
2005-12-30
Epub
2005-00-19
Pages
42655-42668
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC3910375
Subset
IM
Grants
NIA NIH HHS · AG/NS17485 · United States
NINDS NIH HHS · R01 NS041786 · United States
NINDS NIH HHS · R01 NS060872 · United States
NIEHS NIH HHS · R01 ES015567 · United States
NINDS NIH HHS · NS41786 · United States
External Links
PubMed source DOI: 10.1074/jbc.M505910200 PMC Full Text View journal details
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