Similar patterns of mitochondrial vulnerability and rescue induced by genetic modification of alpha-synuclein, parkin, and DJ-1 in Caenorhabditis elegans.
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.
Ved
Rina
R
Deparment of Pharmacology, Boston University School of Medicine.
Saha
Shamol
S
Deparment of Pharmacology, Boston University School of Medicine.
Westlund
Beth
B
Deparment of Cambria Biosciences, Boston University School of Medicine.
Perier
Celine
C
Hoffmann-La Roche, Columbia University.
Burnam
Lucinda
L
Deparment of Cambria Biosciences, Boston University School of Medicine.
Sluder
Anne
A
Deparment of Cambria Biosciences, Boston University School of Medicine.
Hoener
Marius
M
Neurology Institute, Columbia University.
Rodrigues
Cecilia Mp
CM
Centro de Patogenese Molecular, Faculty of Pharmacy, University of Lisbon.
Alfonso
Aixa
A
Dept. of Biological Science, University of Illinois.
Steer
Clifford
C
Dept. of Medicine, University of Minnesota.
Liu
Leo
L
Deparment of Cambria Biosciences, Boston University School of Medicine.
Przedborski
Serge
S
Hoffmann-La Roche, Columbia University.
Wolozin
Benjamin
B
Deparment of Pharmacology, Boston University School of Medicine.
D020155:3-Hydroxybutyric Acid / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D001565:Benzoates / Q000494:pharmacology; D052160:Benzothiazoles; D001647:Bile Acids and Salts / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000378:metabolism*; D002756:Cholagogues and Choleretics / Q000494:pharmacology; D003300:Copper / Q000737:chemistry; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors; D017353:Gene Deletion; D005786:Gene Expression Regulation; D015723:Gene Library; D005821:Genetic Techniques; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins; D007477:Ions; D007501:Iron / Q000737:chemistry; D008928:Mitochondria / Q000378:metabolism*; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics*; D010101:Oxygen Consumption; D010269:Paraquat / Q000494:pharmacology; D010300:Parkinson Disease / Q000473:pathology; D011090:Polyenes / Q000494:pharmacology; D011341:Probucol / Q000494:pharmacology; D000071617:Protein Deglycase DJ-1; D011720:Pyrazoles / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D019810:Sodium Azide / Q000494:pharmacology; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D019076:Transgenes; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D051844:alpha-Synuclein / Q000235:genetics*
D000975:Antioxidants; D001565:Benzoates; D052160:Benzothiazoles; D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D047908:Intracellular Signaling Peptides and Proteins; D007477:Ions; D015513:Oncogene Proteins; D011090:Polyenes; D011720:Pyrazoles; D011724:Pyridazines; D034741:RNA, Small Interfering; D013844:Thiazoles; D051844:alpha-Synuclein; D012402:Rotenone; C009462:thioflavin T; C428725:pyridaben; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D003300:Copper; C041573:stigmatellin; D019810:Sodium Azide; C415144:fenpyroximate; D007501:Iron; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D042967:Electron Transport Complex I; D011341:Probucol; D010269:Paraquat; D020155:3-Hydroxybutyric Acid