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bioRxiv · 10.1101/2025.10.10.681644

Complement Factor H and its C. elegans homolog regulate IFT52/OSM-6 and CNG channel localization in sensory neurons

Oshima, Y.·Hussey, K.·Hagen, J.·Smit-McBride, Z.·Moorthy, M.·Matsubara, J. A.·Flajnik, M.·Johnston, R. J.·Vogel, B. E.
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Abstract

Age-related macular degeneration (AMD), the leading cause of blindness in the elderly, is characterized by progressive degeneration of retinal photoreceptors. Current disease models propose AMD pathogenesis is a consequence of cytolytic damage and tissue inflammation that result from defective repression of alternative complement pathway activity by complement factor H (CFH). However, recent studies demonstrate functions for CFH that are outside of its established role in the alternative complement pathway, suggesting that novel CFH-mediated mechanisms may influence AMD initiation and progression. Our previous demonstration that CFH and its nematode homolog, CFH-1, modulate inversin/NPHP-2 accumulation in vertebrate photoreceptor and C. elegans sensory neuron cilia during aging suggests that AMD patients with CFH loss-of-function mutations have cilia defects that may contribute to photoreceptor dysfunction. Here, we investigate the consequences of CFH and CFH-1 loss-of-function mutations on the dynamics and localization of intraflagellar transport (IFT) train and visual cycle components in these cells. In C. elegans sensory neurons, IFTB1 components IFT52/OSM-6 and IFT88/OSM-5 are transported at similar rates in WT animals but IFT52/OSM-6 transport slows significantly in cfh-1 mutant animals while IFT88/OSM-5 is unaffected. Defective localization of IFT52/OSM-6 in photoreceptors of CFH knockout mice and in human photoreceptors from AMD high-risk CFH Y402H homozygotes, suggest an evolutionarily conserved role for CFH in promoting IFT52/OSM-6 transport and localization in sensory neuron cilia. In addition, distribution of CNG channel subunits in C. elegans cfh-1 mutant sensory neurons and CFH Y402H high-risk human photoreceptors are distinct from their WT and Y402 low-risk counterparts. Together, the data indicate previously unappreciated functions for CFH in IFT train organization and cilia protein localization and suggest a novel mechanism for photoreceptor segment thinning, an early AMD biomarker that has been linked to CFH high-risk variants.

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Oshima, Y., Hussey, K., Hagen, J., Smit-McBride, Z., Moorthy, M., Matsubara, J. A., Flajnik, M., Johnston, R. J., Vogel, B. E.. 2025-10-13. Complement Factor H and its C. elegans homolog regulate IFT52/OSM-6 and CNG channel localization in sensory neurons. https://doi.org/10.1101/2025.10.10.681644

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