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A genetic temperature switch hints at possible treatment of ciliopathies

Figure: Zoomed-in view of the mutated region of the dynein molecular motor structure. The mutation results in a temperature-sensitive defect in the formation and function of cilia, the sensory structures present on most cells in the human body and associated with many human disorders. The pink structure is ATP, the yellow ball is Mg2+, and the amino acid mutated (from glycine to glutamic acid; yellow) is shown in yellow. The neighboring amino acid (aspartic acid; green), is essential for ATP binding/hydrolysis. 

 

A genetic temperature switch hints at possible treatment of ciliopathies

The experiment – The Leroux group and collaborators used fluorescence microscopy to observe a type of free-living nematode (roundworm) called Caenorhabditis elegans that was treated with a mutagen called ethyl methanesulfonate (EMS), and identified mutants whose sensory neurons were no longer able to detect environmental cues. They suspected that these mutants had defects in cilia, the small antenna-like sensory structures that are present at the ends of neuronal projections.

The discovery – One of the mutants, identified by whole-genome sequencing, was discovered to be temperature-sensitive: its cilia were normal at 15°C, but largely impaired at 25°C. The authors used this temperature-sensitive cilia mutant, the first to be uncovered in a multicellular animal, to demonstrate an important role for dynein, a key biomolecule that acts as a ‘molecular motor’ to maintain the structural integrity and function of cilia. By turning the dynein motor on or off at different temperatures, the authors showed that even as the animals age, cilia function on neurons and elsewhere could be at least partially restored.

Its significance – Numerous human disorders arise from cilia dysfunction, called ciliopathies. Collectively, ciliopathies affect nearly every organ in the body, causing clinical ailments such as blindness, obesity, polycystic kidney disease, skeletal anomalies, and brain malformations. The current findings have implications for the potential post-natal treatment of ciliopathies; for example, repairing a genetic mutation in a gene important for cilium structure and function early during development could help prevent blindness, or polycystic kidney disease in adulthood. More generally, the work unveils a fundamental role for dynein in the formation of cilia, and more specifically, a diffusion barrier (or ‘gate’) called a transition zone, which the Leroux lab previously showed is important in regulating the internal composition of ‘homeostasis ‘of the ciliary compartment.

Read the paper“Role for intraflagellar transport in building a functional transition zone” by Jensen, VL; Lambacher, NJ; Li, CM; Mohan, S; Williams, CL; Inglis, PN; Yoder, BK; Blacque, OE; Leroux, MR. EMBO Reports 19(12):e45862 (2018). DOI: 10.15252/embr.201845862.

 

Website article compiled by Jacqueline Watson with Theresa Kitos