Oxidative stress alters the regulatory control of p66Shc and Akt in PINK1 deficient cells.
Mitochondrial dysfunction is involved in the underlying pathology of Parkinson's Disease (PD). PINK1 deficiency, which gives rise to familial early-onset PD, is associated with this dysfunction as well as increased oxidative stress. We have established primary fibroblast cell lines from two patients with PD who carry mutations in the PINK1 gene. The phosphorylation of Akt is abrogated in the presence of oxidative stressors in the complete absence of PINK1 suggesting enhanced apoptotic signalling. We have found an imbalance between the production of reactive oxygen species where the capacity of the cell to remove these toxins by anti-oxidative enzymes is greatly reduced. The expression levels of the anti-oxidant enzymes glutathione peroxidase-1, MnSOD, peroxiredoxin-3 and thioredoxin-2 were diminished. The p66(Shc) adaptor protein has recently been identified to become activated by oxidative stress by phosphorylation at residue Ser36 which then translocates to the mitochondrial inner membrane space. The phosphorylation of p66(Shc) at Ser36 is significantly increased in PINK1 deficient cell lines under normal tissue culture conditions, further still in the presence of compounds which elicit oxidative stress. The stable transfection of PINK1 in the fibroblasts which display the null phenotype ameliorates the hyper-phosphorylation of p66(Shc).
Maj
Mary C
MC
Metabolism Research Programme, Research Institute, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada M5G 1X8.
Tkachyova
Ilona
I
Patel
Pratik
P
Addis
Jane B
JB
Mackay
Nevena
N
Levandovskiy
Valeriy
V
Lee
Jisoo
J
Lang
Anthony E
AE
Cameron
Jessie M
JM
Robinson
Brian H
BH
D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000378:metabolism*; D054464:Peroxiredoxins / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013482:Superoxide Dismutase / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1; D000099202:PTEN-Induced Putative Kinase
D005979:Glutathione Peroxidase; D054464:Peroxiredoxins; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D012694:Serine; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013482:Superoxide Dismutase; D013879:Thioredoxins; D000094765:Glutathione Peroxidase GPX1; D000099202:PTEN-Induced Putative Kinase; C528024:SHC1 protein, human; C000722067:GPX1 protein, human