Kir6.2 Deficiency Promotes Mesencephalic Neural Precursor Cell Differentiation via Regulating miR-133b/GDNF in a Parkinson’s Disease Mouse Model
The loss of dopaminergic (DA) neurons in the substantia nigra (SN) is a major feature in the pathology of Parkinson’s disease (PD). Using neural stem or progenitor cells (NSC/NPCs), the prospect of replacing the missing or damaged DA neurons is very attractive for PD therapy. However, little is known about the endogenous mechanisms and molecular pathways regulating the NSC/NPC proliferation and differentiation in the development of PD. Herein, using Kir6.2 knockout (Kir6.2−/−) mice, we observed that genetic deficiency of Kir6.2 exacerbated the loss of SN DA neurons relatively early in a chronic MPTP/probenecid (MPTP/p) injection course, but rescued the damage of neurons 7 days after the last MPTP/p injection. Meanwhile, we found that Kir6.2 knockout predominantly increased the differentiation of nuclear receptor-related 1 (Nurr1+) precursors to DA neurons, indicating that Kir6.2 deficiency could activate an endogenous self-repair process. Furthermore, we demonstrated in vivo and in vitro that lack of Kir6.2 promoted neuronal differentiation via inhibiting the downregulation of glia cell line-derived neurotrophic factor (GDNF), which negatively related to the level of microRNA-133b. Notably, we revealed that Gdnf is a target gene of miR-133b and transfection of miR-133b could attenuate the enhancement of neural precursor differentiation induced by Kir6.2 deficiency. Collectively, we clarify for the first time that Kir6.2/K-ATP channel functions as a novel endogenous negative regulator of NPC differentiation, and provide a promising neuroprotective target for PD therapeutics.
KeywordsKir6.2/K-ATP Adult neurogenesis Nurr1+ precursors Differentiation miR-133b Parkinson’s disease
Compliance with Ethical Standards
All animal experiments were performed in accordance with the institutional guidelines for animal use and care, and the study protocol was approved by the ethical committee of Nanjing Medical University.
Conflict of Interest
The authors declare that they have no conflict of interest.
- 2.Toda T, Gage FH (2017) Review: adult neurogenesis contributes to hippocampal plasticity. Cell Tissue Res. https://doi.org/10.1007/s00441-017-2735-4
- 8.Lu KT, Huang TC, Wang JY, You YS, Chou JL, Chan MW, Wo PY, Amstislavskaya TG et al (2015) NKCC1 mediates traumatic brain injury-induced hippocampal neurogenesis through CREB phosphorylation and HIF-1alpha expression. Pflugers Arch 467(8):1651–1661. https://doi.org/10.1007/s00424-014-1588-x CrossRefPubMedGoogle Scholar
- 10.Shen KZ, Wu YN, Munhall AC, Johnson SW (2016) AMP kinase regulates ligand-gated K-ATP channels in substantia nigra dopamine neurons. Neuroscience 330:219–228. https://doi.org/10.1016/j.neuroscience.2016.06.001 CrossRefPubMedPubMedCentralGoogle Scholar
- 11.Knowlton CJ, Kutterer S, Roeper J, Canavier CC (2017) Calcium dynamics control K-ATP channel mediated bursting in substantia nigra dopamine neurons: a combined experimental and modeling study. J Neurophysiol. https://doi.org/10.1152/jn.00351.2017
- 12.Duda J, Potschke C, Liss B (2016) Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson’s disease. J Neurochem 139(Suppl 1):156–178. https://doi.org/10.1111/jnc.13572 CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Wang S, Hu LF, Yang Y, Ding JH, Hu G (2005) Studies of ATP-sensitive potassium channels on 6-hydroxydopamine and haloperidol rat models of Parkinson’s disease: implications for treating Parkinson’s disease? Neuropharmacology 48(7):984–992. https://doi.org/10.1016/j.neuropharm.2005.01.009 CrossRefPubMedGoogle Scholar
- 18.Przedborski S, Tieu K, Perier C, Vila M (2004) MPTP as a mitochondrial neurotoxic model of Parkinson’s disease. J Bioenerg Biomembr 36(4):375–379. https://doi.org/10.1023/B:JOBB.0000041771.66775.d5 CrossRefPubMedGoogle Scholar
- 20.Sairanen M, Lucas G, Ernfors P, Castren M, Castren E (2005) Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus. J Neurosci 25(5):1089–1094. https://doi.org/10.1523/JNEUROSCI.3741-04.2005 CrossRefPubMedGoogle Scholar
- 21.Castelo-Branco G, Wagner J, Rodriguez FJ, Kele J, Sousa K, Rawal N, Pasolli HA, Fuchs E et al (2003) Differential regulation of midbrain dopaminergic neuron development by Wnt-1, Wnt-3a, and Wnt-5a. Proc Natl Acad Sci U S A 100(22):12747–12752. https://doi.org/10.1073/pnas.1534900100 CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Spathis AD, Asvos X, Ziavra D, Karampelas T, Topouzis S, Cournia Z, Qing X, Alexakos P et al (2017) Nurr1:RXRalpha heterodimer activation as monotherapy for Parkinson’s disease. Proc Natl Acad Sci U S A 114(15):3999–4004. https://doi.org/10.1073/pnas.1616874114 CrossRefPubMedPubMedCentralGoogle Scholar
- 27.L'Episcopo F, Serapide MF, Tirolo C, Testa N, Caniglia S, Morale MC, Pluchino S, Marchetti B (2011) A Wnt1 regulated frizzled-1/beta-catenin signaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: therapeutical relevance for neuron survival and neuroprotection. Mol Neurodegener 6:49. https://doi.org/10.1186/1750-1326-6-49 CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Maxwell SL, Ho HY, Kuehner E, Zhao S, Li M (2005) Pitx3 regulates tyrosine hydroxylase expression in the substantia nigra and identifies a subgroup of mesencephalic dopaminergic progenitor neurons during mouse development. Dev Biol 282(2):467–479. https://doi.org/10.1016/j.ydbio.2005.03.028 CrossRefPubMedGoogle Scholar
- 30.Leggio L, Vivarelli S, L'Episcopo F, Tirolo C, Caniglia S, Testa N, Marchetti B, Iraci N (2017) microRNAs in Parkinson’s disease: from pathogenesis to novel diagnostic and therapeutic approaches. Int J Mol Sci 18(12). https://doi.org/10.3390/ijms18122698