Linking ADSL and GRK4 to ciliopathies of the nervous system and the kidney

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Dokumentart: PhDThesis
Date: 2023-06-07
Language: English
Faculty: 4 Medizinische Fakultät
Department: Medizin
Advisor: Philipp, Melanie (Prof. Dr.)
Day of Oral Examination: 2023-05-12
DDC Classifikation: 570 - Life sciences; biology
Other Keywords: Ziliopathien
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Cilia are highly conserved antennae-like structures that are involved in many developmental processes and signaling. Malformations of cilia are often associated with clinical phenotypes like microcephaly, infertility, edema formation, congenital heart defects or renal abnormalities (1). These diseases are known as ciliopathies. In the last years, the number of genes that cause ciliopathies increased. For potential treatment of ciliopathies, it is important to better understand cilia function and signaling. This work identified two novel regulators of cilium biogenesis, namely Adenylosuccinate lyase (ADSL) and G protein-coupled receptor kinase 4 (GRK4). Genetic variants of ADSL predispose to a condition termed ADSL deficiency (ADSLD). Patients suffering from ADSLD show a broad spectrum of clinical phenotypes, reaching from psychomotor delay, mental retardation or microcephaly to hyperactivity. We found that several of these phenotypes are associated to dysfunctional cilia. Molecularly, the accumulation of the toxic intermediate SAICAr affects cilia structure and function. Beside this we also found that enhanced DNA damage after loss of Adsl came from the lack of nucleosides and not from the accumulation of SAICAr . Taken together, these results showed that we have pathway-specific phenotypes of ADSLD. Further research is important for a better understanding of the complex pathology of ADSLD. Furthermore, we discovered GRK4 also as a new regulator of kidney development ciliogenesis. Up to date, genetic variants of GRK4, that are found in patients suffering from high blood pressure, are often associated with a hyperactivity towards dopamine receptors. Here we showed that GRK4 extends its function, independently of its kinase activity. We postulate that GRK4 regulates mechanistic target of rapamycin (mTOR) signaling. Affecting mTOR led to a related phenotype like the GRK4 depletion, namely cilia elongation and dysfunctional kidneys in the zebrafish embryos. We were able to reproduce our results in human and murine cells. Interestingly, we found that the genetic variants of GRK4 failed to rescue any of the observed phenotypes. Further studies are important to identify potential interaction partners of GRK4 and how GRK4 influences mTOR signaling.

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