scholarly journals Faculty Opinions recommendation of A pathway for Parkinson's Disease LRRK2 kinase to block primary cilia and Sonic hedgehog signaling in the brain.

2019 ◽  
Author(s):  
Mitsunori Fukuda ◽  
Norihiko Ohbayashi
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Sonic Hedgehog Signaling ◽  
Lrrk2 Kinase ◽  
The Brain

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

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Herschel S Dhekne ◽  
Izumi Yanatori ◽  
Rachel C Gomez ◽  
Francesca Tonelli ◽  
Federico Diez ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Sonic Hedgehog ◽  
Transcriptional Activation ◽  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Cultured Cells ◽  
Editorial Note ◽  
Rab Gtpases ◽  
Lrrk2 Kinase

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 (<xref ref-type="decision-letter" rid="SA1">see decision letter</xref>).

scholarly journals A novel role for primary cilia in airway remodeling

2017 ◽  
Vol 313 (2) ◽  
pp. L328-L338 ◽  
Author(s):  
Carol S. Trempus ◽  
Weifeng Song ◽  
Ahmed Lazrak ◽  
Zhihong Yu ◽  
Judy R. Creighton ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Calcium Influx ◽  
Airway Remodeling ◽  
Critical Role ◽  
Calcium Flux ◽  
Airway Smooth Muscle Cells ◽  
Mechanical Stimuli ◽  
Sonic Hedgehog Signaling

Primary cilia (PC) are solitary cellular organelles that play critical roles in development, homeostasis, and disease pathogenesis by modulating key signaling pathways such as Sonic Hedgehog and calcium flux. The antenna-like shape of PC enables them also to facilitate sensing of extracellular and mechanical stimuli into the cell, and a critical role for PC has been described for mesenchymal cells such as chondrocytes. However, nothing is known about the role of PC in airway smooth muscle cells (ASMCs) in the context of airway remodeling. We hypothesized that PC on ASMCs mediate cell contraction and are thus integral in the remodeling process. We found that PC are expressed on ASMCs in asthmatic lungs. Using pharmacological and genetic methods, we demonstrated that PC are necessary for ASMC contraction in a collagen gel three-dimensional model both in the absence of external stimulus and in response to the extracellular component hyaluronan. Mechanistically, we demonstrate that the effect of PC on ASMC contraction is, to a small extent, due to their effect on Sonic Hedgehog signaling and, to a larger extent, due to their effect on calcium influx and membrane depolarization. In conclusion, PC are necessary for the development of airway remodeling by mediating calcium flux and Sonic Hedgehog signaling.

scholarly journals ARL13B regulates Sonic Hedgehog signaling from outside primary cilia

2019 ◽  
Author(s):  
Eduardo D. Gigante ◽  
Megan R. Taylor ◽  
Anna A. Ivanova ◽  
Richard A. Kahn ◽  
Tamara Caspary
Keyword(s):  
Signal Transduction ◽  
Sonic Hedgehog ◽  
Protein Trafficking ◽  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Complete Loss ◽  
Wild Type ◽  
Sonic Hedgehog Signaling ◽  
Biochemical Function

AbstractARL13B is a regulatory GTPase highly enriched in cilia. Complete loss of Arl13b disrupts cilia architecture, protein trafficking and Sonic hedgehog signaling. To determine whether ARL13B is required within cilia, we knocked in a cilia-excluded variant of ARL13B (V358A) and showed it retains all known biochemical function. We found that ARL13BV358A protein was expressed but could not be detected in cilia, even when retrograde ciliary transport was blocked. We showed Arl13bV358A/V358A mice are viable and fertile with normal Shh signal transduction. However, in contrast to wild type cilia, Arl13bV358A/V358A cells displayed short cilia and lacked ciliary ARL3 and INPP5E. These data indicate that ARL13B’s role within cilia can be uncoupled from its function outside of cilia. Furthermore, these data imply that the cilia defects upon complete absence of ARL13B do not underlie the alterations in Shh transduction, which is unexpected given the requirement of cilia for Shh transduction.

scholarly journals Author response: ARL13B regulates Sonic hedgehog signaling from outside primary cilia

2019 ◽  
Author(s):  
Eduardo D Gigante ◽  
Megan R Taylor ◽  
Anna A Ivanova ◽  
Richard A Kahn ◽  
Tamara Caspary
Keyword(s):  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Author Response ◽  
Sonic Hedgehog Signaling

scholarly journals ARL13B regulates Sonic hedgehog signaling from outside primary cilia

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Eduardo D Gigante ◽  
Megan R Taylor ◽  
Anna A Ivanova ◽  
Richard A Kahn ◽  
Tamara Caspary
Keyword(s):  
Signal Transduction ◽  
Sonic Hedgehog ◽  
Protein Trafficking ◽  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Complete Loss ◽  
Wild Type ◽  
Sonic Hedgehog Signaling ◽  
Biochemical Function

ARL13B is a regulatory GTPase highly enriched in cilia. Complete loss of Arl13b disrupts cilia architecture, protein trafficking and Sonic hedgehog signaling. To determine whether ARL13B is required within cilia, we knocked in a cilia-excluded variant of ARL13B (V358A) and showed it retains all known biochemical function. We found that ARL13BV358A protein was expressed but could not be detected in cilia, even when retrograde ciliary transport was blocked. We showed Arl13bV358A/V358A mice are viable and fertile with normal Shh signal transduction. However, in contrast to wild type cilia, Arl13bV358A/V358A cells displayed short cilia and lacked ciliary ARL3 and INPP5E. These data indicate that ARL13B’s role within cilia can be uncoupled from its function outside of cilia. Furthermore, these data imply that the cilia defects upon complete absence of ARL13B do not underlie the alterations in Shh transduction, which is unexpected given the requirement of cilia for Shh transduction.

scholarly journals Trisomy 21 induces pericentrosomal crowding disrupting early stages of primary ciliogenesis and mouse cerebellar development

2021 ◽  
Author(s):  
Cayla E Jewett ◽  
Bailey L McCurdy ◽  
Eileen T O'Toole ◽  
Katherine S Given ◽  
Carrie H Lin ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Sonic Hedgehog ◽  
Trisomy 21 ◽  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Chromosome 21 ◽  
Sonic Hedgehog Signaling ◽  
Trafficking Defects ◽  
Microtubule Networks

Primary cilia are signaling organelles essential for development and homeostasis. Loss of primary cilia is lethal, and decreased or defective cilia cause multisystemic conditions called ciliopathies. Down syndrome shares clinical overlap with ciliopathies. We previously showed that trisomy 21 diminishes primary cilia formation and function due to elevated Pericentrin, a centrosome protein encoded on chromosome 21. Pericentrin is mislocalized, creating aggregates that disrupt pericentrosomal trafficking and microtubule organization. Here, we examine the cilia-related molecules and pathways disrupted in trisomy 21 and their in vivo phenotypic relevance. Utilizing ciliogenesis time course experiments, we reveal how Pericentrin, microtubule networks, and components of ciliary vesicles are reorganized for ciliogenesis in euploid cells. Early in ciliogenesis, chromosome 21 polyploidy results in elevated Pericentrin and microtubule networks away from the centrosome that ensnare MyosinVA and EHD1, blocking mother centriole uncapping that is essential for ciliogenesis. Ciliated trisomy 21 cells have persistent trafficking defects that reduce transition zone protein localization, which is critical for Sonic hedgehog signaling. Sonic hedgehog signaling is decreased and anticorrelates with Pericentrin levels in trisomy 21 primary mouse embryonic fibroblasts. Finally, we observe decreased ciliation in vivo. A mouse model of Down syndrome with elevated Pericentrin has fewer primary cilia in cerebellar granule neuron progenitors and thinner external granular layers. Our work reveals that elevated Pericentrin in trisomy 21 disrupts multiple early steps of ciliogenesis and creates persistent trafficking defects in ciliated cells. This pericentrosomal crowding results in signaling defects consistent with the neurological deficits found in individuals with Down syndrome.

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