gms | German Medical Science

Photoreceptors are high-end neurosensory cells, able to detect light on a single photon level, discriminate colors, and turn light into an electrical signal, transmitted to the brain. Photoreceptors realize this performance through their outer segments that contain para-cristaline arrays of light receptive visual pigments compartmentalized in membrane staples called outer segment disks. Outer segments as well as disks are generated and maintained via motor driven, directional ciliary transport from the inner- to the light sensitive outer segments, which enable us to see. Mutations that critically affect outer segment formation and function impair eyesight and eventually lead to photoreceptor degeneration.

Combining and integrating several layers of information gathering from proteome centric biochemistry, in silico network analysis as well as structural biology we have developed an analytical approach to determine components of the molecular machinery exerting these functions as well as to identify functional constraints in the corresponding protein networks that drive them and – when hit by mutation – result in disease. As a result of this approach, we have generated a multiscale model that defines key elements of photoreceptor outer segment function on the molecular level.

We have spotlighted protein transport from the inner- to the outer segment as an essential process generating the light receptive outer segment. Zooming in on a protein mutated in an early childhood blinding disease, LCA5, we have identified the interflagellar transport machinery as the physical entity driving vesicular trafficking through the interconnecting cilium that bridges the inner and the outer segment. We have modeled the impact of mutation on the level of functional protein networks and can show, that specific physical interactions affecting the functionality of discrete molecular machines are rendered dysfunctional by these mutations. The resulting information not only offers a deeper understanding on the impact of mutations, but allows to gain a comprehensive view on the molecular mechanisms of photoreceptor outer segment formation and renewal. Further, it suggests novel signaling routes guiding these activities. Our model demonstrates a specific disease susceptibility of the core visual pathway as well as the transport machinery and a relative robustness of other functional modules. This information can serve as a basis for elucidating physiological principles as well as to enable targeted molecular medicine and rational pharmacology to treat retinal degenerative diseases in the future.

The SYSCILIA consortium: a European Community‘s Seventh Framework Programme FP7/2009 under grant agreement no: 241955, SYSCILIA; http://syscilia.org.