title: Response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) differs in mouse strains and reveals a divergence in JNK signaling and COX-2 induction prior to loss of neurons in the substantia nigra pars compacta.
abstract: Parkinson's disease (PD) is a neurodegenerative disease whose hallmark pathological features include a selective loss of dopaminergic neurons in the midbrain. Recent studies have described the activation of a stress-induced signal cascade, c-Jun N-terminal kinase (JNK)-mediated activation of c-Jun, and an increase in the expression of a downstream effector, cyclooxygenase 2 (COX-2), in postmortem PD brains. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which induces selective neuronal loss in the midbrain similar to that seen in PD, also induces JNK-mediated activation of c-Jun and generates a COX-2 response in C57BL/6J mice. However, mice exhibit a strain-dependent susceptibility to MPTP. Identifying the point(s) of molecular divergence in the MPTP-induced response may provide insight into the cause of PD or a means to identify susceptibility to PD in humans. Here we examined JNK signaling and COX-2 induction in two strains of mice, the MPTP-sensitive C57BL/6J and the MPTP-resistant Swiss Webster (SW). We show that C57BL/6J and SW strains differ in JNK and c-Jun activation in response to MPTP. In addition, the MPTP-induced COX-2 response occurs exclusively in C57BL/6J mice. Furthermore, strain-specific responses to MPTP are not due to differences in MPP(+) levels and are not secondary to cell death. These results provide evidence toward a mechanism of strain-dependent sensitivity to MPTP.
authors: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, Tennessee 38105, USA.
authors: Justin D
authors: JD
authors: Boyd
authors: Haeman
authors: H
authors: Jang
authors: Kennie R
authors: KR
authors: Shepherd
authors: Ciaran
authors: C
authors: Faherty
authors: Sally
authors: S
authors: Slack
authors: Yun
authors: Y
authors: Jiao
authors: Richard J
authors: RJ
authors: Smeyne
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009498:Neurotoxins / Q000494:pharmacology; D020734:Parkinsonian Disorders / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013045:Species Specificity; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology
chemical_list: D009498:Neurotoxins; D016755:Proto-Oncogene Proteins c-jun; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D051546:Cyclooxygenase 2; D048031:JNK Mitogen-Activated Protein Kinases