Looking beyond cilia in renal ciliopathies

Abstract

In this work, I have investigated the group of inherited diseases called “ciliopathies”, involving defects in proteins localizing to the cilium or associated complexes and pathways. The main focus of this thesis was to unravel molecular and cell biological mechanisms playing a role in ciliopathy development. The first symptoms of ciliopathies are visible at a young age, sometimes even before birth; besides developmental anomalies, tissue degeneration takes place at early-onset, and often affects the kidneys of these young patients. Since renal degeneration including fibrosis and cyst growth rapidly leads to renal end-stage disease, usually before the age of 20, the patients require a donor kidney or dialysis until transplantation can be arranged. This thesis describes several novel aspects of the renal ciliopathy field: (1) Optimizing new sources of patient cells to model ciliopathies ex vivo; (2) Identification of new ion channel genes which affect renal cilia; (3) The mechanism of disease involving both ciliary and nuclear functions of ciliopathy gene products, supplying a novel layer to the disease mechanism, and (4) Potential solutions to target renal cysts and fibrosis development to slow down disease progression and postpone kidney transplantation.

The model that loss of ciliary structure or function leads to ciliopathies appears to be an oversimplified model. From the work presented in this thesis we can conclude that there is another layer to the disease mechanism. We propose that upstream events could play a role in tissue degeneration, initiated by replication stress and DNA damage response signalling. Whether replication stress is underlying all renal or extra-renal manifestations of ciliopathies remains to be investigated. Differences in extra-ciliary protein functions among the NPHP proteins might be at least part of the explanation why the different ciliopathies have different clinical manifestations. In addition, the extent of ciliary and nuclear dysfunction could be related to the variability between ciliopathies. The ciliary research field is rapidly evolving, with new genes, new signalling networks and new ciliopathies being identified, implicating the importance of proper functioning of the primary cilium and highlights the need for therapeutic intervention. Collaborations between clinicians, molecular biologists and bioinformaticians are required to examine the complexity of the cilium in the future to obtain a better understanding of ciliopathies, with as ultimate goal to define treatment strategies. Looking beyond the cilium and focusing on alternative mechanisms of disease etiology is opening an exciting new chapter for ‘ciliopathy’ research.