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

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 earl...

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Autores principales: Khan, Shahzad S, Sobu, Yuriko, Dhekne, Herschel S, Tonelli, Francesca, Berndsen, Kerryn, Alessi, Dario R, Pfeffer, Suzanne R
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8550758/
https://www.ncbi.nlm.nih.gov/pubmed/34658337
http://dx.doi.org/10.7554/eLife.67900
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author Khan, Shahzad S
Sobu, Yuriko
Dhekne, Herschel S
Tonelli, Francesca
Berndsen, Kerryn
Alessi, Dario R
Pfeffer, Suzanne R
author_facet Khan, Shahzad S
Sobu, Yuriko
Dhekne, Herschel S
Tonelli, Francesca
Berndsen, Kerryn
Alessi, Dario R
Pfeffer, Suzanne R
author_sort Khan, Shahzad S
collection PubMed
description 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.
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spelling pubmed-85507582021-10-29 Pathogenic LRRK2 control of primary cilia and Hedgehog signaling in neurons and astrocytes of mouse brain Khan, Shahzad S Sobu, Yuriko Dhekne, Herschel S Tonelli, Francesca Berndsen, Kerryn Alessi, Dario R Pfeffer, Suzanne R eLife Cell Biology 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. eLife Sciences Publications, Ltd 2021-10-18 /pmc/articles/PMC8550758/ /pubmed/34658337 http://dx.doi.org/10.7554/eLife.67900 Text en © 2021, Khan et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cell Biology
Khan, Shahzad S
Sobu, Yuriko
Dhekne, Herschel S
Tonelli, Francesca
Berndsen, Kerryn
Alessi, Dario R
Pfeffer, Suzanne R
Pathogenic LRRK2 control of primary cilia and Hedgehog signaling in neurons and astrocytes of mouse brain
title Pathogenic LRRK2 control of primary cilia and Hedgehog signaling in neurons and astrocytes of mouse brain
title_full Pathogenic LRRK2 control of primary cilia and Hedgehog signaling in neurons and astrocytes of mouse brain
title_fullStr Pathogenic LRRK2 control of primary cilia and Hedgehog signaling in neurons and astrocytes of mouse brain
title_full_unstemmed Pathogenic LRRK2 control of primary cilia and Hedgehog signaling in neurons and astrocytes of mouse brain
title_short Pathogenic LRRK2 control of primary cilia and Hedgehog signaling in neurons and astrocytes of mouse brain
title_sort pathogenic lrrk2 control of primary cilia and hedgehog signaling in neurons and astrocytes of mouse brain
topic Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8550758/
https://www.ncbi.nlm.nih.gov/pubmed/34658337
http://dx.doi.org/10.7554/eLife.67900
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