DJ-1 expression modulates astrocyte-mediated protection against neuronal oxidative stress.
DJ-1 deficiency is a cause of genetic Parkinson's disease (PARK7 PD). In sporadic Parkinson's disease (PD), however, DJ-1 is abundantly expressed in reactive astrocytes. This may represent a compensatory protective response. In initial support of this hypothesis, we have shown in vitro that DJ-1-overexpressing astrocytes protect neurons against rotenone-induced death. Rotenone, a pesticide linked to increased PD risk, can stimulate oxidative stress. This process is implicated in PD pathogenesis. Since DJ-1 can enhance antioxidant systems, we hypothesized that augmenting its expression in astrocytes would protect cocultured neurons against oxidative stress. We report here that DJ-1-overexpressing astrocytes were significantly more protective against rotenone-induced neuronal thiol oxidation than wild-type astrocytes in neuron-astrocyte cocultures. DJ-1-knockdown astrocytes, on the other hand, were significantly impaired in their capacity to protect neurons against thiol oxidation. Each of these findings was replicated using astrocyte-conditioned media on neuron-enriched cultures. Thus, DJ-1-modulated, astrocyte-released soluble factors must be involved in the mechanism. This is the first demonstration that the manipulation of a PD-causing gene in astrocytes affects their ability to protect neurons against oxidative stress.
Department of Neurology and Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Steven J
SJ
Mullett
Roberto
R
Di Maio
J Timothy
JT
Greenamyre
David A
DA
Hinkle
D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D002478:Cells, Cultured / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology; D018920:Coculture Techniques; D005786:Gene Expression Regulation; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000378:metabolism; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D013438:Sulfhydryl Compounds / Q000633:toxicity; D014162:Transfection
D015513:Oncogene Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D013438:Sulfhydryl Compounds; D054464:Peroxiredoxins; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1