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
Affiliations
Rasem Mustafa
Institute of Anatomy and Cell Biology, Heidelberg Medical Faculty, University of Heidelberg, 69120 Heidelberg, Germany
Chahinaz Rawas
Institute of Applied Physiology, Ulm Medical Faculty, University of Ulm, 89081 Ulm, Germany
Nadja Mannal
Institute of Applied Physiology, Ulm Medical Faculty, University of Ulm, 89081 Ulm, Germany
Grzegorz Kreiner
Department of Brain Biochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Kraków, Poland
Björn Spittau
Institute of Anatomy and Cell Biology, Department of Molecular Embryology, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
Katarzyna Kamińska
Department of Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Kraków, Poland
Rüstem Yilmaz
Mannheim Center for Translational Neuroscience, Division of Neurodegenerative Disorders, Department of Neurology, Mannheim Medical Faculty, University of Heidelberg, 68167 Mannheim, Germany
Christina Pötschke
Institute of Applied Physiology, Ulm Medical Faculty, University of Ulm, 89081 Ulm, Germany
Joachim Kirsch
Institute of Anatomy and Cell Biology, Heidelberg Medical Faculty, University of Heidelberg, 69120 Heidelberg, Germany
Birgit Liss
Institute of Applied Physiology, Ulm Medical Faculty, University of Ulm, 89081 Ulm, Germany
Kerry L. Tucker
Institute of Anatomy and Cell Biology, Heidelberg Medical Faculty, University of Heidelberg, 69120 Heidelberg, Germany
Rosanna Parlato
Institute of Anatomy and Cell Biology, Heidelberg Medical Faculty, University of Heidelberg, 69120 Heidelberg, Germany
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.
