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

Dhekne, H. S., Yanatori, I., Gomez, R. C., Tonelli, F., Diez, F., Schule, B., et al. (2018). A pathway for Parkinson's Disease LRRK2 kinase to block primary cilia and Sonic hedgehog signaling in the brain. eLife, 7: e40202. doi:10.7554/eLife.40202.

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elife-40202-v1.pdf (Publisher version), 6MB
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© 2018, Dhekne et al.

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 Creators:
Dhekne, Herschel S1, Author
Yanatori, Izumi1, Author
Gomez, Rachel C1, Author
Tonelli, Francesca1, Author
Diez, Federico1, Author
Schule, Birgitt1, Author
Steger, Martin2, Author              
Alessi, Dario R1, Author
Pfeffer, Suzanne R1, Author
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1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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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.

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 Dates: 2018
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: ISI: 30398148
DOI: 10.7554/eLife.40202
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Title: eLife
Source Genre: Journal
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Publ. Info: Cambridge : eLife Sciences Publications
Pages: - Volume / Issue: 7 Sequence Number: e40202 Start / End Page: - Identifier: ISSN: 2050-084X
CoNE: https://pure.mpg.de/cone/journals/resource/2050-084X