Mutations disrupting ciliary assembly and trafficking are a common cause of inherited retinal degenerations, causing early-onset severe blindness. Bardet-Biedl syndrome (BBS) is one of the human genetic diseases associated with defective ciliary trafficking and photoreceptor degeneration. However, details of the patho-mechanisms underlying photoreceptor degeneration in BBS are largely unknown and no effective treatment options have been developed. The long-term goal of this research program is to elucidate the molecular and cellular mechanisms of photoreceptor degeneration in BBS and develop therapeutic interventions to preserve vision in BBS patients. Our prior study determined that accumulation of proteins in the outer segment (OS) is likely the primary cause of photoreceptor degeneration in BBS, representing a novel mechanism of photoreceptor degeneration. During the next grant cycle, we will explore how protein accumulation in the OS induces photoreceptor degeneration. Our preliminary data suggest that OS accumulation/sequestration of Stx3 (a SNARE protein facilitating membrane fusion events) and proteasomal overload stress are involved. The proposed study will determine how these factors contribute to photoreceptor degeneration in BBS. The outcome of this study will greatly advance our understanding of the cilia-related retinopathies and provide an important foundation for the development of mechanism-based therapies.

Public Health Relevance

Inherited retinal degenerations due to defective protein trafficking in photoreceptor cells causes severe blindness in children and young adults, but no treatment options are available. In the proposed study, we will determine the mechanisms of retinal degeneration in Bardet-Biedl syndrome (BBS), a human genetic disease associated with defective protein trafficking. This study will provide critical insights into the mechanisms of photoreceptor degeneration and open up new treatment strategies for BBS and potentially other inherited retinal degenerations that share common disease mechanisms.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology of the Visual System Study Section (BVS)
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Neuhold, Lisa
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University of Iowa
Schools of Medicine
Iowa City
United States
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Weihbrecht, Katie; Goar, Wesley A; Carter, Calvin S et al. (2018) Genotypic and phenotypic characterization of the Sdccag8Tn(sb-Tyr)2161B.CA1C2Ove mouse model. PLoS One 13:e0192755
Hsu, Ying; Garrison, Janelle E; Kim, Gunhee et al. (2017) BBSome function is required for both the morphogenesis and maintenance of the photoreceptor outer segment. PLoS Genet 13:e1007057
Seo, Seongjin; Datta, Poppy (2017) Photoreceptor outer segment as a sink for membrane proteins: hypothesis and implications in retinal ciliopathies. Hum Mol Genet 26:R75-R82
Bullard, Steven A; Seo, Seongjin; Schilling, Birgit et al. (2016) Gadd45a Protein Promotes Skeletal Muscle Atrophy by Forming a Complex with the Protein Kinase MEKK4. J Biol Chem 291:17496-17509
Dutta, Nirmal; Seo, Seongjin (2016) RPGR, a prenylated retinal ciliopathy protein, is targeted to cilia in a prenylation- and PDE6D-dependent manner. Biol Open 5:1283-9
Datta, Poppy; Allamargot, Chantal; Hudson, Joseph S et al. (2015) Accumulation of non-outer segment proteins in the outer segment underlies photoreceptor degeneration in Bardet-Biedl syndrome. Proc Natl Acad Sci U S A 112:E4400-9
Lee, Je-Jung; Seo, Seongjin (2015) PDE6D binds to the C-terminus of RPGR in a prenylation-dependent manner. EMBO Rep 16:1581-2
Plotnikova, Olga V; Seo, Seongjin; Cottle, Denny L et al. (2015) INPP5E interacts with AURKA, linking phosphoinositide signaling to primary cilium stability. J Cell Sci 128:364-72
Zhang, Yan; Seo, Seongjin; Bhattarai, Sajag et al. (2014) BBS mutations modify phenotypic expression of CEP290-related ciliopathies. Hum Mol Genet 23:40-51
Chamling, Xitiz; Seo, Seongjin; Searby, Charles C et al. (2014) The centriolar satellite protein AZI1 interacts with BBS4 and regulates ciliary trafficking of the BBSome. PLoS Genet 10:e1004083

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