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

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

doi:10.3390/antiox10081284

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.

Highlights

Primary cilia (PC) are non-motile microtubule-based cellular antennas that arise at the plasma membrane of most mammalian cell types during growth arrest [1,2]
In order to investigate the cell-autonomous role of PC in differentiated DA neurons, we conditionally ablated the Ift88 gene with the Cre-loxP recombination system
We show that PC are required for the maintenance of Substantia nigra (SN) DA neurons and for nigrostriatal integrity

Summary

Introduction

Primary cilia (PC) are non-motile microtubule-based cellular antennas that arise at the plasma membrane of most mammalian cell types during growth arrest [1,2]. Antioxidants 2021, 10, 1284 sess an axoneme, a microtubular structure that extends from the basal body and it is surrounded by a specialized plasma membrane. They include axoneme-based transport machinery called intraflagellar transport (IFT), which uses different motor protein complexes for anterograde versus retrograde transport [3]. Due to their small volume and high enrichment in membrane receptors, PC represent a crucial hub for the coordination of multiple signaling pathways, and play a critical role in tissue differentiation and homeostasis [2]. Type II diabetes characterized by increased blood glucose and insulin resistance seems to increase the risk to develop

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