Abstract
Dopamine loss and motor deficits in Parkinson’s disease typically commence unilaterally and remain asymmetric for many years, raising the possibility that endogenous defenses slow the cross-hemispheric transmission of pathology. It is well-established that the biological response to subtoxic stress prepares cells to survive subsequent toxic challenges, a phenomenon known as preconditioning, tolerance, or stress adaptation. Here we demonstrate that unilateral striatal infusions of the oxidative toxicant 6-hydroxydopamine (6-OHDA) precondition the contralateral nigrostriatal pathway against the toxicity of a second 6-OHDA infusion in the opposite hemisphere. 6-OHDA-induced loss of dopaminergic terminals in the contralateral striatum was ablated by cross-hemispheric preconditioning, as shown by two independent markers of the dopaminergic phenotype, each measured by two blinded observers. Similarly, loss of dopaminergic somata in the contralateral substantia nigra was also abolished, according to two blinded measurements. Motor asymmetries in floor landings, forelimb contacts with a wall, and spontaneous turning behavior were consistent with these histological observations. Unilateral 6-OHDA infusions increased phosphorylation of the kinase ERK2 and expression of the antioxidant enzyme CuZn superoxide dismutase in both striata, consistent with our previous mechanistic work showing that these two proteins mediate preconditioning in dopaminergic cells. These findings support the existence of cross-hemispheric preconditioning in Parkinson’s disease and suggest that dopaminergic neurons mount impressive natural defenses, despite their reputation as being vulnerable to oxidative injury. If these results generalize to humans, Parkinson’s pathology may progress slowly and asymmetrically because exposure to a disease-precipitating insult induces bilateral upregulation of endogenous defenses and elicits cross-hemispheric preconditioning.
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Abbreviations
- 6-OHDA:
-
6-Hydroxydopamine
- GAP43:
-
Growth-associated protein 43
- PBS:
-
Phosphate-buffered saline
- DAT:
-
Dopamine transporter
- CuZnSOD:
-
CuZn superoxide dismutase
- MnSOD:
-
Manganese superoxide dismutase
- TBS:
-
Tris-buffered saline
- TH:
-
Tyrosine hydroxylase
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Acknowledgements
Designed the experiments and wrote the paper: RKL. Performed the experiments and generated the figures: JW. Analyzed the data: JW, MC, KM, TB, DH, DP, and NN. We are grateful to Deborah Willson and Jackie Farrer for excellent administrative support and the Denise Butler-Buccilli and Christine Close for outstanding animal care. Funded by awards to RKL from the Hillman Family Foundation (GRANT109033) and the National Institutes of Health (R15NS093539).
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429_2017_1552_MOESM1_ESM.tif
Supplemental Fig. 1: Reproducibility of motor and histological assessments. Measurements shown in graphs from the main text were repeated by a blinded observer. (A-B) The second blinded assessment of landing behavior was consistent with the first blinded assessment shown in Fig. 1E-F of the main text. The second assessments of (C) striatal TH and (D) striatal DAT were consistent with the first assessments shown in Figs. 3C and 3F, respectively. (E) The second assessment of nigral cell numbers was consistent with the first assessments shown in Fig. 4E. * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001 left versus right hemisphere or turns; a p ≤ 0.05, aa p ≤ 0.01 versus group a; b p ≤ 0.05, bb p ≤ 0.01, bbb p ≤ 0.001 versus group b; two-way ANOVA followed by Bonferroni post hoc correction (TIFF 1146 kb)
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Supplemental Fig. 2: Raw measurements of two independent dopaminergic markers in the striatum. Tyrosine hydroxylase (TH) and dopamine transporter (DAT) measurements shown in the main text in Figs. 3A and 3E were based on the raw immunofluorescent values shown here in panels A and B, respectively. Note that the effect sizes and p values are identical for the raw and percentage data. *** p ≤ 0.001 left versus right hemisphere; a p ≤ 0.05, aa p ≤ 0.01, aaa p ≤ 0.001 versus group a; bb p ≤ 0.01, bbb p ≤ 0.001 versus group b; two-way ANOVA followed by Bonferroni post hoc correction (TIFF 695 kb)
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Supplemental Fig. 3: Zoomable version of Fig. 4. See main text for legend. Note that the images of the ventral midbrain are very large in size because each montage was stitched together from multiple high-resolution photos captured with a 10 × objective. Therefore, the cellular features in the photomicrograph take time to populate on the computer screen, sometimes up to several minutes. Note that there may be computer-introduced imperfections at the boundaries of the stitches. All tissue was processed in parallel with the same solutions. Images from all four groups were captured at the same exposure and intensity scaling. The intensity scaling is relatively high so that even weakly labeled TH+ cells can be visualized (TIFF 60145 kb)
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Weilnau, J.N., Carcella, M.A., Miner, K.M. et al. Evidence for cross-hemispheric preconditioning in experimental Parkinson’s disease. Brain Struct Funct 223, 1255–1273 (2018). https://doi.org/10.1007/s00429-017-1552-6
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DOI: https://doi.org/10.1007/s00429-017-1552-6