Seminar

Errors of Development: control of proteostasis in rare diseases

Rosa Barrio

The development of higher eukaryotes requires the strict spatial and temporal control of gene expression and cell signaling. Regulation of protein homeostasis via posttranslational modifications (PTMs) by members of the ubiquitin-like family (UbL) plays an essential role in this process. When proteostasis is compromised, inborn errors of development might occur, as seen in multiple rare diseases. UbLs can also influence organelle function, such as the centrosome and primary cilia. In the Barrio lab, we study PTMs in relation to rare diseases, especially those linked to primary cilia malfunction, as is the case of Townes-Brocks syndrome. TBS is caused by a dominantly-acting truncate of the transcriptional repressor Spalt-like1 (SALL1), which interferes with proteostatic regulation of key cilia regulators. Insights into TBS etiology may lead to future therapies to alleviate late-onset symptoms (hearing loss, kidney failure), improving quality of life for this neglected rare disease. As UbL-modifications are scarce and dynamic, we develop novel technology to study them, including biotin-based proximity proteomics strategies to study the processes that are compromised in TBS. These strategies are applicable to any protein and disease scenario.