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

Rasem Mustafa; Chahinaz Rawas; Nadja Mannal; Grzegorz Kreiner; Björn Spittau; Katarzyna Kamińska; Rüstem Yilmaz; Christina Pötschke; Joachim Kirsch; Birgit Liss; Kerry L Tucker; Rosanna Parlato

doi:10.3390/antiox10081284

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

Antioxidants (Basel). 2021 Aug 13;10(8):1284. doi: 10.3390/antiox10081284.

Authors

Rasem Mustafa^{1

2}, Chahinaz Rawas², Nadja Mannal², Grzegorz Kreiner³, Björn Spittau^{4

5}, Katarzyna Kamińska^{6

7}, Rüstem Yilmaz⁸, Christina Pötschke², Joachim Kirsch¹, Birgit Liss^{2

9}, Kerry L Tucker^{1

10

11}, Rosanna Parlato^{1

2

8}

Affiliations

¹ Institute of Anatomy and Cell Biology, Heidelberg Medical Faculty, University of Heidelberg, 69120 Heidelberg, Germany.
² Institute of Applied Physiology, Ulm Medical Faculty, University of Ulm, 89081 Ulm, Germany.
³ Department of Brain Biochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Kraków, Poland.
⁴ Institute of Anatomy and Cell Biology, Department of Molecular Embryology, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.
⁵ Anatomy and Cell Biology, Medical School OWL, Bielefeld University, 33615 Bielefeld, Germany.
⁶ Department of Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Kraków, Poland.
⁷ Jagiellonian Center for Experimental Therapeutics, Jagiellonian University, Bobrzynskiego 14, 30-348 Kraków, Poland.
⁸ Mannheim Center for Translational Neuroscience, Division of Neurodegenerative Disorders, Department of Neurology, Mannheim Medical Faculty, University of Heidelberg, 68167 Mannheim, Germany.
⁹ Linacre College and New College, University of Oxford, Oxford OX1 2JD, UK.
¹⁰ Department of Biomedical Sciences, College of Osteopathic Medicine, Biddeford, ME 04005, USA.
¹¹ Center for Excellence in the Neurosciences, University of New England, Biddeford, ME 04005, USA.

Abstract

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.

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

Grants and funding

PA 1529/2-1/Deutsche Forschungsgemeinschaft