Absence of nigral degeneration in aged parkin/DJ-1/PINK1 triple knockout mice.
Recessively inherited loss-of-function mutations in the parkin, DJ-1, or PINK1 gene are linked to familial cases of early-onset Parkinson's diseases (PD), and heterozygous mutations are associated with increased incidence of late-onset PD. We previously reported that single knockout mice lacking Parkin, DJ-1, or PINK1 exhibited no nigral degeneration, even though evoked dopamine release from nigrostriatal terminals was reduced and striatal synaptic plasticity was impaired. In this study, we tested whether inactivation of all three recessive PD genes, each of which was required for nigral neuron survival in the aging human brain, resulted in nigral degeneration during the lifespan of mice. Surprisingly, we found that triple knockout mice lacking Parkin, DJ-1, and PINK1 have normal morphology and numbers of dopaminergic and noradrenergic neurons in the substantia nigra and locus coeruleus, respectively, at the ages of 3, 16, and 24 months. Interestingly, levels of striatal dopamine in triple knockout mice were normal at 16 months of age but increased at 24 months. These results demonstrate that inactivation of all three recessive PD genes is insufficient to cause significant nigral degeneration within the lifespan of mice, suggesting that these genes may be protective rather than essential for the survival of dopaminergic neurons during the aging process. These findings also support the notion that mammalian Parkin and PINK1 may function in the same genetic pathway as in Drosophila.
Kitada
Tohru
T
Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusets, USA.
Tong
Youren
Y
Gautier
Clement A
CA
Shen
Jie
J
D000367:Age Factors; D000818:Animals; D002452:Cell Count / Q000379:methods; D004298:Dopamine / Q000378:metabolism; D004563:Electrochemistry / Q000379:methods; D008125:Locus Coeruleus / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000235:genetics*; D009474:Neurons / Q000502:physiology*; D008771:Nordefrin / Q000378:metabolism; D015513:Oncogene Proteins / Q000172:deficiency*; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases / Q000172:deficiency*; D013378:Substantia Nigra / Q000473:pathology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency*; D000099202:PTEN-Induced Putative Kinase
D004298:Dopamine; D008771:Nordefrin; D015513:Oncogene Proteins; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases; D014446:Tyrosine 3-Monooxygenase; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein; C503466:PARK7 protein, mouse
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