4.7 Article

Targeted Ablation of Primary Cilia in Differentiated Dopaminergic Neurons Reduces Striatal Dopamine and Responsiveness to Metabolic Stress

期刊

ANTIOXIDANTS
卷 10, 期 8, 页码 -

出版社

MDPI
DOI: 10.3390/antiox10081284

关键词

primary cilium; intraflagellary protein; substantia nigra; striatum; dopamine; pacemaker; multielecotrode arrays (MEA); D2-autoreceptor

资金

  1. An-Najah National University (Nablus, Palestine)
  2. University of New England
  3. Polish National Science Center [2017/25/B/NZ7/02406]
  4. Maj Institute Pharmacology
  5. Krupp Foundation
  6. DFG [PA 1529/2-1, LI 1754/1-2]
  7. University of Ulm PhD Fellowship
  8. FWF [F-4412]

向作者/读者索取更多资源

Primary cilia play a crucial role in maintaining vulnerable dopaminergic neurons in Parkinson's disease, regulating their spontaneous activity and susceptibility to neurotoxic substances. These findings highlight the significance of primary cilia in dopamine system disorders and stress responses.
Primary cilia (PC) are microtubule-based protrusions of the cell membrane transducing molecular signals during brain development. Here, we report that PC are required for maintenance of Substantia nigra (SN) dopaminergic (DA) neurons highly vulnerable in Parkinson's disease (PD). Targeted blockage of ciliogenesis in differentiated DA neurons impaired striato-nigral integrity in adult mice. The relative number of SN DA neurons displaying a typical auto-inhibition of spontaneous activity in response to dopamine was elevated under control metabolic conditions, but not under metabolic stress. Strikingly, in the absence of PC, the remaining SN DA neurons were less vulnerable to the PD neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP). Our data indicate conserved PC-dependent neuroadaptive responses to DA lesions in the striatum. Moreover, PC control the integrity and dopamine response of a subtype of SN DA neurons. These results reinforce the critical role of PC as sensors of metabolic stress in PD and other disorders of the dopamine system.

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