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Pathogenic LRRK2 control of primary cilia and Hedgehog signaling in neurons and astrocytes of mouse brain

Authors :
Kerryn Berndsen
Yuriko Sobu
Suzanne R. Pfeffer
Francesca Tonelli
Shahzad S. Khan
Herschel S. Dhekne
Dario R. Alessi
Source :
eLife, eLife, Vol 10 (2021)
Publication Year :
2021
Publisher :
Cold Spring Harbor Laboratory, 2021.

Abstract

Activating LRRK2 mutations cause Parkinson’s disease, and pathogenic LRRK2 kinase interferes with ciliogenesis. Previously, we showed that cholinergic interneurons of the dorsal striatum lose their cilia in R1441C LRRK2 mutant mice (Dhekne et al., 2018). Here, we show that cilia loss is seen as early as 10 weeks of age in these mice and also in two other mouse strains carrying the most common human G2019S LRRK2 mutation. Loss of the PPM1H phosphatase that is specific for LRRK2-phosphorylated Rab GTPases yields the same cilia loss phenotype seen in mice expressing pathogenic LRRK2 kinase, strongly supporting a connection between Rab GTPase phosphorylation and cilia loss. Moreover, astrocytes throughout the striatum show a ciliation defect in all LRRK2 and PPM1H mutant models examined. Hedgehog signaling requires cilia, and loss of cilia in LRRK2 mutant rodents correlates with dysregulation of Hedgehog signaling as monitored by in situ hybridization of Gli1 and Gdnf transcripts. Dopaminergic neurons of the substantia nigra secrete a Hedgehog signal that is sensed in the striatum to trigger neuroprotection; our data support a model in which LRRK2 and PPM1H mutant mice show altered responses to critical Hedgehog signals in the nigrostriatal pathway.

Details

Database :
OpenAIRE
Journal :
eLife, eLife, Vol 10 (2021)
Accession number :
edsair.doi.dedup.....8c3b2dad335bdd8d99f1faa2491fcf6c
Full Text :
https://doi.org/10.1101/2021.03.02.433576