Neurodegeneration, Neuroprotection, and Disease-Oriented NeuroscienceResearch PaperHeat shock protein 70 kDa over-expression and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced nigrostriatal degeneration in mice
Highlights
▶Hsp70 over-expression fails to suppress MPTP-induced neuronal death in mice substantia nigra. ▶HSP70 is unable to prevent MPTP-induced nigrostriatal axon terminal degeneration. ▶HSP70 does not improve nigrostriatal axon terminal recovery subsequent to MPTP treatment. ▶In conclusion, HSP70 alone is not sufficient to protect against neurotoxic parkinsonism in mice.
Section snippets
Animals and MPTP treatments
Wild-type and mice over-expressing Hsp70 (Marber et al., 1995) were housed at regulated temperature (22±1 °C) in a 12 h light/dark cycle with ad libitum access to food and drink. All experiments were performed in accordance with the European Communities Council Directive of 24 November 1986 (86/609/EEC) to minimize animal's pain and discomfort, and this study was approved by the ethical committee in the “Hospital Universitario Virgen del Rocío.” Hsp70 transgenic mice were used in which rat
Characterization of Hsp70 transgene expression
It was first determined whether the Hsp70 transgene was expressed after backcrossing the transgenic mice to the C57BL/6 strain. As determined by western blot analysis (Fig. 1A), HSP70 protein level was almost non-detectable in either striatum or VM of wild-type mice, whereas a protein band immunoreactive to HSP70 was clearly detected in both brain regions of transgenic animals. These results demonstrated that over-expression of Hsp70 transgene was conserved in transgenic mice after backcrossing.
Discussion
Molecular chaperones, such as HSP70s, not only play important roles in protein folding and degradation, but also contribute to antioxidant defense and anti-apoptotic pathways, which are clearly implicated in the pathogenesis of PD. In the current study, using MPTP to mimic parkinsonism in mice, it was found that ubiquitous transgenic over-expression of Hsp70 did not suppress MPTP-induced nigrostriatal dopaminergic neuronal damage at either the somata or the axon terminals. Moreover, Hsp70
Conclusion
Our results demonstrate that HSP70 alone is not sufficient to protect against MPTP-induced moderate to severe neurotoxicity in mice. On the other hand, it is still not clear whether Hsp70 over-expression or activation could be used as a therapeutic approach in PD patients and needs to be further studied.
Acknowledgments
We would like to thank Dr. Brian Scott for his help with the Hsp70 mice, Dr. José Antonio Rodriguez for his help with the HPLC experiments, Ms. Ma Nela Suárez Luna for her help with MPTP treatment, and Dr. Alberto Pascual for his critical reading of the manuscript. This work was supported by grants from the Spanish Ministerio de Educación y Ciencia (J.L.-B.; SAF2006/08311), Fundación Marcelino Botín (J.L.-B.), and Fundación Juan March (J.L.-B.). L.G. was also supported by Instituto de Salud
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