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Pathogenic LRRK2 control of primary cilia and Hedgehog signaling in neurons and astrocytes of mouse brain
- 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.
- Subjects :
- Male
Mouse
QH301-705.5
Science
Nigrostriatal pathway
Substantia nigra
In situ hybridization
GTPase
Biology
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
General Biochemistry, Genetics and Molecular Biology
Mice
primary cilia
GLI1
Ciliogenesis
Glial cell line-derived neurotrophic factor
medicine
Animals
Hedgehog Proteins
Cilia
Biology (General)
Hedgehog
Neurons
General Immunology and Microbiology
General Neuroscience
Cilium
Brain
Cell Biology
General Medicine
hedgehog signaling
LRRK2 kinase
Hedgehog signaling pathway
nervous system diseases
Cell biology
medicine.anatomical_structure
Astrocytes
parkinson's disease
biology.protein
Medicine
Phosphorylation
Female
Rab
Research Advance
Rab GTPase
nigro-striatal pathway
Signal Transduction
Neuroscience
Subjects
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