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A complement factor H homolog, heparan sulfation, and syndecan maintain inversin compartment boundaries in C. elegans
Natalie Acker1, Harold Smith2, Claire Devine1
1Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, University of Maryland, Baltimore, MD 21201.
Insights
A study in C. elegans reveals complement factor H (CFH) has a novel role in sensory neuron cilia, maintaining protein localization and potentially impacting age-related macular degeneration (AMD) progression.
Area of Science:
- Neuroscience
- Genetics
- Ophthalmology
Background:
- Age-related macular degeneration (AMD) is a primary cause of vision loss in older adults.
- Canonical models implicate complement factor H (CFH) and heparan sulfate (HS) interactions in AMD pathogenesis.
- Noncanonical mechanisms involving CFH-HS interactions may also drive AMD progression.
Purpose of the Study:
- To investigate the noncanonical functions of CFH in sensory neurons.
- To explore the role of CFH in maintaining cilia structure and protein localization in aging.
- To determine if these functions are conserved in vertebrate sensory neurons.
Main Methods:
- Utilized the nematode C. elegans as a model organism.
- Examined the localization of a CFH homolog in CEP mechanosensory neuron cilia.
- Investigated the roles of HS 3-O sulfotransferase (HST-3.1) and syndecan (SDN-1) in CFH function.
- Analyzed inversin/NPHP-2 localization in C. elegans, mouse, and human photoreceptors.
Main Results:
- A C. elegans CFH homolog localizes to cilia of mechanosensory neurons.
- CFH maintains inversin/NPHP-2 localization within proximal cilia compartments in aging adults.
- HS 3-O sulfotransferase HST-3.1 and syndecan SDN-1 are essential for CFH localization and inversin/NPHP-2 compartment integrity.
- CFH mutations in mouse and human photoreceptors show defective inversin/NPHP-2 localization.
Conclusions:
- CFH plays a noncanonical role in maintaining sensory neuron cilia integrity.
- Defects in cilia structure due to CFH dysfunction may contribute to photoreceptor degeneration in AMD.
- These findings suggest conserved functions of CFH in vertebrate sensory neurons and potential new therapeutic targets for AMD.
Abstract:
Age-related macular degeneration (AMD) is a leading cause of blindness among the elderly. Canonical disease models suggest that defective interactions between complement factor H (CFH) and cell surface heparan sulfate (HS) result in increased alternative complement pathway activity, cytolytic damage, and tissue inflammation in the retina. Although these factors are thought to contribute to increased disease risk, multiple studies indicate that noncanonical mechanisms that result from defective CFH and HS interaction may contribute to the progression of AMD as well. A total of 60 ciliated sensory neurons in the nematode Caenorhabditis elegans detect chemical, olfactory, mechanical, and thermal cues in the environment. Here, we find that a C. elegans CFH homolog localizes on CEP mechanosensory neuron cilia where it has noncanonical roles in maintaining inversin/NPHP-2 within its namesake proximal compartment and preventing inversin/NPHP-2 accumulation in distal cilia compartments in aging adults. CFH localization and maintenance of inversin/NPHP-2 compartment integrity depend on the HS 3-O sulfotransferase HST-3.1 and the transmembrane proteoglycan syndecan/SDN-1. Defective inversin/NPHP-2 localization in mouse and human photoreceptors with CFH mutations indicates that these functions and interactions may be conserved in vertebrate sensory neurons, suggesting that previously unappreciated defects in cilia structure may contribute to the progressive photoreceptor dysfunction associated with CFH loss-of-function mutations in some AMD patients.
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