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

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.

Developmental pathways linked to the vulnerability of adult midbrain dopaminergic neurons to neurodegeneration

“…Their enhanced biogenesis and elongation under increased mitochondrial oxidative stress conditions (MPTP lesioning) appeared to exert a neuroprotective effect by augmenting the autophagic removal of dysfunctional mitochondria and suppressing the apoptotic death of these neurons ( Bae et al, 2019 ). These results were partly corroborated by a recent study showing that the cKO of a crucial structural and functional component of the PC in maturing mDA neurons ( Dat - Ift88 mice) resulted in the loss of approximately 20% SNc DA neurons and a corresponding decrease of striatal mDA innervation and DA content, as well as an increase of PC length in striatal neurons ( Mustafa et al, 2021 ). The reduction of SNc DA neuron numbers in the Dat - Ift88 cKO mice was not further accentuated by MPTP treatment ( Mustafa et al, 2021 ), in contrast to the report by Bae et al (2019) .…”

“…These results were partly corroborated by a recent study showing that the cKO of a crucial structural and functional component of the PC in maturing mDA neurons ( Dat - Ift88 mice) resulted in the loss of approximately 20% SNc DA neurons and a corresponding decrease of striatal mDA innervation and DA content, as well as an increase of PC length in striatal neurons ( Mustafa et al, 2021 ). The reduction of SNc DA neuron numbers in the Dat - Ift88 cKO mice was not further accentuated by MPTP treatment ( Mustafa et al, 2021 ), in contrast to the report by Bae et al (2019) . The most likely explanation for these discrepancies are methodological differences (constitutive genetic ablation vs. viral OE-mediated knockdown of the PC component, and subchronic vs. acute administration of MPTP) between the two studies ( Bae et al, 2019 ; Mustafa et al, 2021 ).…”

“…The reduction of SNc DA neuron numbers in the Dat - Ift88 cKO mice was not further accentuated by MPTP treatment ( Mustafa et al, 2021 ), in contrast to the report by Bae et al (2019) . The most likely explanation for these discrepancies are methodological differences (constitutive genetic ablation vs. viral OE-mediated knockdown of the PC component, and subchronic vs. acute administration of MPTP) between the two studies ( Bae et al, 2019 ; Mustafa et al, 2021 ). Mustafa et al (2021) also proposed that the loss of SNc DA neurons in the Dat - Ift88 cKO mutants affected primarily a PC-bearing subset of these neurons displaying a high intrinsic electrophysiological activity that can be further stimulated by DA, which might therefore be particularly prone to metabolic stress and degeneration.…”

“…Smo cKO in striatal cholinergic INs or Shh cKO in young mDA neurons resulted in the progressive worsening of LIDs despite the lack of an mDA phenotype in these mice, whereas the OE of a constitutively active SMO protein in a genetic PD mouse model blocked the appearance and intensification of LIDs despite the severe mDA phenotype of these animals (Malave et al, 2021). In an elegant series of experiments, Malave et al (2021) showed that the repeated optogenetic stimulation of mDA burst firing led to LID-like behavior intensification in an L-DOPA-independent manner. This was most likely due to the exhaustion of SHH signaling from the mDA neurons to the striatal cholinergic INs, because a single dose of the antagonist cyclopamine prior to stimulation onset exacerbated, whereas the agonist SAG blocked this effect.…”

Oxidative Stress in Neurodegenerative Diseases

“…Another original research article by Mustafa R. et al focused on understanding the role of the primary cilium, a specialized protrusion of the plasma membrane, for the maintenance of dopaminergic neurons under basal conditions and upon induction of mitochondrial and oxidative stress in a pharmacological mouse model of PD [4]. By generating a mutant mouse line that lacked primary cilia in dopaminergic neurons, this study shows that primary cilia may play a role in the auto-inhibitory action of dopamine on dopaminergic neuron spontaneous activity and that dopaminergic neurons are in part protected by the neurotoxic effect of PD-toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP), an inhibitor of the mitochondrial complex I activity.…”