A pathway for Parkinson's Disease LRRK2 kinase to block primary cilia and Sonic hedgehog signaling in the brain

Herschel S. Dhekne, Izumi Yanatori, Rachel C. Gomez, Francesca Tonelli, Federico Diez, Birgitt Schüle, Martin Steger, Dario R. Alessi, Suzanne R. Pfeffer (Lead / Corresponding author)

Research output: Contribution to journalArticle

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Abstract

Parkinson's disease-associated LRRK2 kinase phosphorylates multiple Rab GTPases, including Rab8A and Rab10. We show here that LRRK2 kinase interferes with primary cilia formation in cultured cells, human LRRK2 G2019S iPS cells and in the cortex of LRRK2 R1441C mice. Rab10 phosphorylation strengthens its intrinsic ability to block ciliogenesis by enhancing binding to RILPL1. Importantly, the ability of LRRK2 to interfere with ciliogenesis requires both Rab10 and RILPL1 proteins. Pathogenic LRRK2 influences the ability of cells to respond to cilia-dependent, Hedgehog signaling as monitored by Gli1 transcriptional activation. Moreover, cholinergic neurons in the striatum of LRRK2 R1441C mice show decreased ciliation, which will decrease their ability to sense Sonic hedgehog in a neuro-protective circuit that supports dopaminergic neurons. These data reveal a molecular pathway for regulating cilia function that likely contributes to Parkinson's disease-specific pathology.

Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Original languageEnglish
Article numbere40202
Pages (from-to)1-26
Number of pages26
JournaleLife
Volume7
DOIs
Publication statusPublished - 6 Nov 2018

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Aptitude
Hedgehogs
Cilia
Neurons
Parkinson Disease
Brain
Phosphotransferases
rab GTP-Binding Proteins
Phosphorylation
Pathology
Cholinergic Agents
Chemical activation
Cells
Cholinergic Neurons
Peer Review
Networks (circuits)
Dopaminergic Neurons
Transcriptional Activation
Cultured Cells
Proteins

Cite this

Dhekne, H. S., Yanatori, I., Gomez, R. C., Tonelli, F., Diez, F., Schüle, B., ... Pfeffer, S. R. (2018). A pathway for Parkinson's Disease LRRK2 kinase to block primary cilia and Sonic hedgehog signaling in the brain. eLife, 7, 1-26. [e40202]. https://doi.org/10.7554/eLife.40202
Dhekne, Herschel S. ; Yanatori, Izumi ; Gomez, Rachel C. ; Tonelli, Francesca ; Diez, Federico ; Schüle, Birgitt ; Steger, Martin ; Alessi, Dario R. ; Pfeffer, Suzanne R. / A pathway for Parkinson's Disease LRRK2 kinase to block primary cilia and Sonic hedgehog signaling in the brain. In: eLife. 2018 ; Vol. 7. pp. 1-26.
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abstract = "Parkinson's disease-associated LRRK2 kinase phosphorylates multiple Rab GTPases, including Rab8A and Rab10. We show here that LRRK2 kinase interferes with primary cilia formation in cultured cells, human LRRK2 G2019S iPS cells and in the cortex of LRRK2 R1441C mice. Rab10 phosphorylation strengthens its intrinsic ability to block ciliogenesis by enhancing binding to RILPL1. Importantly, the ability of LRRK2 to interfere with ciliogenesis requires both Rab10 and RILPL1 proteins. Pathogenic LRRK2 influences the ability of cells to respond to cilia-dependent, Hedgehog signaling as monitored by Gli1 transcriptional activation. Moreover, cholinergic neurons in the striatum of LRRK2 R1441C mice show decreased ciliation, which will decrease their ability to sense Sonic hedgehog in a neuro-protective circuit that supports dopaminergic neurons. These data reveal a molecular pathway for regulating cilia function that likely contributes to Parkinson's disease-specific pathology.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).",
author = "Dhekne, {Herschel S.} and Izumi Yanatori and Gomez, {Rachel C.} and Francesca Tonelli and Federico Diez and Birgitt Sch{\"u}le and Martin Steger and Alessi, {Dario R.} and Pfeffer, {Suzanne R.}",
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Dhekne, HS, Yanatori, I, Gomez, RC, Tonelli, F, Diez, F, Schüle, B, Steger, M, Alessi, DR & Pfeffer, SR 2018, 'A pathway for Parkinson's Disease LRRK2 kinase to block primary cilia and Sonic hedgehog signaling in the brain', eLife, vol. 7, e40202, pp. 1-26. https://doi.org/10.7554/eLife.40202

A pathway for Parkinson's Disease LRRK2 kinase to block primary cilia and Sonic hedgehog signaling in the brain. / Dhekne, Herschel S.; Yanatori, Izumi; Gomez, Rachel C.; Tonelli, Francesca; Diez, Federico; Schüle, Birgitt; Steger, Martin; Alessi, Dario R.; Pfeffer, Suzanne R. (Lead / Corresponding author).

In: eLife, Vol. 7, e40202, 06.11.2018, p. 1-26.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A pathway for Parkinson's Disease LRRK2 kinase to block primary cilia and Sonic hedgehog signaling in the brain

AU - Dhekne, Herschel S.

AU - Yanatori, Izumi

AU - Gomez, Rachel C.

AU - Tonelli, Francesca

AU - Diez, Federico

AU - Schüle, Birgitt

AU - Steger, Martin

AU - Alessi, Dario R.

AU - Pfeffer, Suzanne R.

N1 - Funding: Michael J. Fox Foundation for Parkinson's Research (LEAPS and RDI); Medical Research Council (MC_UU_12016/2); National Institutes of Health (DK37332).

PY - 2018/11/6

Y1 - 2018/11/6

N2 - Parkinson's disease-associated LRRK2 kinase phosphorylates multiple Rab GTPases, including Rab8A and Rab10. We show here that LRRK2 kinase interferes with primary cilia formation in cultured cells, human LRRK2 G2019S iPS cells and in the cortex of LRRK2 R1441C mice. Rab10 phosphorylation strengthens its intrinsic ability to block ciliogenesis by enhancing binding to RILPL1. Importantly, the ability of LRRK2 to interfere with ciliogenesis requires both Rab10 and RILPL1 proteins. Pathogenic LRRK2 influences the ability of cells to respond to cilia-dependent, Hedgehog signaling as monitored by Gli1 transcriptional activation. Moreover, cholinergic neurons in the striatum of LRRK2 R1441C mice show decreased ciliation, which will decrease their ability to sense Sonic hedgehog in a neuro-protective circuit that supports dopaminergic neurons. These data reveal a molecular pathway for regulating cilia function that likely contributes to Parkinson's disease-specific pathology.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

AB - Parkinson's disease-associated LRRK2 kinase phosphorylates multiple Rab GTPases, including Rab8A and Rab10. We show here that LRRK2 kinase interferes with primary cilia formation in cultured cells, human LRRK2 G2019S iPS cells and in the cortex of LRRK2 R1441C mice. Rab10 phosphorylation strengthens its intrinsic ability to block ciliogenesis by enhancing binding to RILPL1. Importantly, the ability of LRRK2 to interfere with ciliogenesis requires both Rab10 and RILPL1 proteins. Pathogenic LRRK2 influences the ability of cells to respond to cilia-dependent, Hedgehog signaling as monitored by Gli1 transcriptional activation. Moreover, cholinergic neurons in the striatum of LRRK2 R1441C mice show decreased ciliation, which will decrease their ability to sense Sonic hedgehog in a neuro-protective circuit that supports dopaminergic neurons. These data reveal a molecular pathway for regulating cilia function that likely contributes to Parkinson's disease-specific pathology.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

U2 - 10.7554/eLife.40202

DO - 10.7554/eLife.40202

M3 - Article

C2 - 30398148

VL - 7

SP - 1

EP - 26

JO - eLife

JF - eLife

SN - 2050-084X

M1 - e40202

ER -