Eupatilin rescues ciliary transition zone defects to ameliorate ciliopathy-related phenotypes

Kim, Yong Joon; Kim, Sung‐Soo; Jung, Yooju; Jung, Eun Ji; Kwon, Ho Jeong; Kim, Joon

doi:10.1172/jci99232

Cited by 37 publications

(37 citation statements)

References 36 publications

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“…However, the treatment of CEP290 -/cells with eupatilin rescues the TZ amount of Nphp5 and ciliary gating since eupatilin inhibits the binding between Nphp5 and calmodulin [71]. In the current study, eupatilin treatment rescued ciliary gating in the Rpgrip1l deficient state ( Figure 4A and B).…”

Section: Discussionsupporting

confidence: 47%

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Rpgrip1l controls ciliary gating by ensuring the proper amount of Cep290 at the vertebrate transition zone

Wiegering

Dildrop

Vesque

et al. 2020

Preprint

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A range of severe human diseases called ciliopathies are caused by the dysfunction of primary cilia. Primary cilia are cytoplasmic protrusions consisting of the basal body (BB), the axoneme and the transition zone (TZ). The BB is a modified mother centriole from which the axoneme, the microtubule-based ciliary scaffold, is formed. At the proximal end of the axoneme, the TZ functions as the ciliary gate governing ciliary protein entry and exit. Since ciliopathies often develop due to mutations in genes encoding proteins that localise to the TZ, the understanding of the mechanisms underlying TZ function is of eminent importance. Here, we show that the ciliopathy protein Rpgrip1l governs ciliary gating by ensuring the proper amount of Cep290 at the vertebrate TZ. Further, we identified the flavonoid eupatilin as a potential agent to tackle ciliopathies caused by mutations in RPGRIP1L as it rescues ciliary gating in the absence of Rpgrip1l.

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Section: Discussionsupporting

confidence: 47%

“…Consequently, Rpgrip1l, Cep290 and Nphp5 can be defined as ciliary gatekeepers. Cep290 binds to Nphp5 thereby preventing the binding of calmodulin to Nphp5 and promoting the recruitment of Nphp5 to the TZ [71]. In the absence of Cep290, Nphp5 is not present at the TZ.…”

Section: Discussionmentioning

confidence: 99%

Rpgrip1l controls ciliary gating by ensuring the proper amount of Cep290 at the vertebrate transition zone

Wiegering

Dildrop

Vesque

et al. 2020

Preprint

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“…Our demonstration of high-content imaging of 661 W cells illustrates the potential utility of this cell line for high-throughput screening. A recent high-throughput small molecule screen in hTERT-RPE1 cells successfully identified eupatilin as a small molecule which rescued transition zone defects in CEP290 knockout RPE1 cells (Kim et al, 2018). A similar approach using 661 W cells could be an even more clinically relevant method for identifying small molecules which could be used for treating retinal ciliopathies.…”

Section: Discussionmentioning

confidence: 99%

661W Photoreceptor Cell Line as a Cell Model for Studying Retinal Ciliopathies

et al. 2019

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The retina contains several ciliated cell types, including the retinal pigment epithelium (RPE) and photoreceptor cells. The photoreceptor cilium is one of the most highly modified sensory cilia in the human body. The outer segment of the photoreceptor is a highly elaborate primary cilium, containing stacks or folds of membrane where the photopigment molecules are located. Perhaps unsurprisingly, defects in cilia often lead to retinal phenotypes, either as part of syndromic conditions involving other organs, or in isolation in the so-called retinal ciliopathies. The study of retinal ciliopathies has been limited by a lack of retinal cell lines. RPE1 retinal pigment epithelial cell line is commonly used in such studies, but the existence of a photoreceptor cell line has largely been neglected in the retinal ciliopathy field. 661W cone photoreceptor cells, derived from mouse, have been widely used as a model for studying macular degeneration, but not described as a model for studying retinal ciliopathies such as retinitis pigmentosa. Here, we characterize the 661W cell line as a model for studying retinal ciliopathies. We fully characterize the expression profile of these cells, using whole transcriptome RNA sequencing, and provide this data on Gene Expression Omnibus for the advantage of the scientific community. We show that these cells express the majority of markers of cone cell origin. Using immunostaining and confocal microscopy, alongside scanning electron microscopy, we show that these cells grow long primary cilia, reminiscent of photoreceptor outer segments, and localize many cilium proteins to the axoneme, membrane and transition zone. We show that siRNA knockdown of cilia genes Ift88 results in loss of cilia, and that this can be assayed by high-throughput screening. We present evidence that the 661W cell line is a useful cell model for studying retinal ciliopathies.

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“…These treatments are still in early development for JS, but have been used for other disorders in humans such as spinal muscular atrophy (Finkel et al, ). Future medications targeting specific pathways that are disrupted in JS may be beneficial, but this work is also in its infancy (Hynes et al, ; Kim et al, ). Some promising medications developed for ciliopathy‐related conditions in animal models have been ineffective or harmful in humans (Ruggenenti et al, ; Serra et al, ; Walz et al, ); therefore, cautious optimism is in order about the timeline for future effective treatments.…”

Section: Methodsmentioning

confidence: 99%

Healthcare recommendations for Joubert syndrome

Bachmann‐Gagescu

Dempsey

Bulgheroni

et al. 2019

American J of Med Genetics Pt A

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Joubert syndrome (JS) is a recessive neurodevelopmental disorder defined by a characteristic cerebellar and brainstem malformation recognizable on axial brain magnetic resonance imaging as the "Molar Tooth Sign". Although defined by the neurological features, JS is associated with clinical features affecting many other organ systems, particularly progressive involvement of the retina, kidney, and liver. JS is a rare condition; therefore, many affected individuals may not have easy access to subspecialty providers familiar with JS (e.g., geneticists, neurologists, developmental pediatricians, ophthalmologists, nephrologists, hepatologists, psychiatrists, therapists, and educators). Expert recommendations can enable practitioners of all types to provide quality care to individuals with JS and know when to refer for subspecialty care. This need will only increase as precision treatments targeting specific genetic causes of JS emerge. The goal of these recommendations is to provide a resource for general practitioners, subspecialists, and families to maximize the health of individuals with JS throughout the lifespan.

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Eupatilin rescues ciliary transition zone defects to ameliorate ciliopathy-related phenotypes

Cited by 37 publications

References 36 publications

Rpgrip1l controls ciliary gating by ensuring the proper amount of Cep290 at the vertebrate transition zone

Rpgrip1l controls ciliary gating by ensuring the proper amount of Cep290 at the vertebrate transition zone

661W Photoreceptor Cell Line as a Cell Model for Studying Retinal Ciliopathies

Healthcare recommendations for Joubert syndrome

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