Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: Critical role for the astrocyte.
Oxidative stress has been implicated in the etiology of Parkinson's disease (PD) and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of PD. It is known that under conditions of oxidative stress, the transcription factor NF-E2-related factor (Nrf2) binds to antioxidant response element (ARE) to induce antioxidant and phase II detoxification enzymes. To investigate the role of Nrf2 in the process of MPTP-induced toxicity, mice expressing the human placental alkaline phosphatase (hPAP) gene driven by a promoter containing a core ARE sequence (ARE-hPAP) were used. ARE-hPAP mice were injected (30 mg/kg) once per day for 5 days and killed 7 days after the last MPTP injection. In response to this design, ARE-dependent gene expression was decreased in striatum whereas it was increased in substantia nigra. The same MPTP protocol was applied in Nrf2(+/+) and Nrf2(-/-) mice; Nrf2 deficiency increases MPTP sensitivity. Furthermore, we evaluated the potential for astrocytic Nrf2 overexpression to protect from MPTP toxicity. Transgenic mice with Nrf2 under control of the astrocyte-specific promoter for the glial fribillary acidic protein (GFAP-Nrf2) on both a Nrf2(+/+) and Nrf2(-/-) background were administered MPTP. In the latter case, only the astrocytes expressed Nrf2. Independent of background, MPTP-mediated toxicity was abolished in GFAP-Nrf2 mice. These striking results indicate that Nrf2 expression restricted to astrocytes is sufficient to protect against MPTP and astrocytic modulation of the Nrf2-ARE pathway is a promising target for therapeutics aimed at reducing or preventing neuronal death in PD.
Chen
Pei-Chun
PC
School of Pharmacy, Molecular and Environmental Toxicology Center, Waisman Center, and Center of Neuroscience, University of Wisconsin, Madison, WI 53705, USA.
Vargas
Marcelo R
MR
Pani
Amar K
AK
Smeyne
Richard J
RJ
Johnson
Delinda A
DA
Kan
Yuet Wai
YW
Johnson
Jeffrey A
JA
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000469:Alkaline Phosphatase / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000473:pathology*; D001483:Base Sequence; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D017931:DNA Primers; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D007150:Immunohistochemistry; D020267:MPTP Poisoning / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000502:physiology*; D010300:Parkinson Disease / Q000473:pathology / Q000503:physiopathology*; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology
D017931:DNA Primers; D005904:Glial Fibrillary Acidic Protein; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000469:Alkaline Phosphatase