Researchers identify lipid responsible for keeping brain fluid moving.


Flagella and cilia are slender organellar protrusions of the eukaryotic cell membrane with sensory and motor function. Flagella and cilia are similar in that they share a microtubule-based cytoskeleton called the axoneme.  Motile cilia and flagella move extracellular fluids and particles, or propel cells such as sperm or unicellular organisms such as the green algae Chlamydomonas reinhardtii. Flagella dysfunction leads to reduced or absent motility and aberrant motile cilia leads to ependymal cell, which contain vital cerebrospinal fluid, malfunction and hydrocephalus.  It is vital for the signaling and motility functions of cilia that length, number, and intraciliary or intraflagellar transport (IFT) of cargo are dynamically regulated.
The protein machinery regulating assembly, length, movement, and transport within these organelles is conserved from Chlamydomonas to mammals. Although cilia and flagella are localized extensions of the plasma mebrane, little is known about the role of lipids in this regulation of ciliogenesis and cilium function.  Now, a study from researchers at Medical College of Georgia has shown that the same lipid, named ceramide, that helps algae swim toward the light also appears to enable one type of brain cell to keep cerebrospinal fluid moving.  The team state that it is important to know how to regulate cilia as they can become dysfunctional by stroke, Alzheimer’s disease, inflammation and aging.  The opensource study is published in the study in the journal Molecular Biology of the Cell.

Previous studies show that in the case of algae, motile cilia work like arms on a swimmer, to help algae reach sunlight, which they use to make sugar for energy and survival.  Motile cilia can make 40-50 whip-like motions per second and are continuously being resorbed and replaced.  These motile cilia also inhabit a type of support brain cell called ependymal cells; the cells that line the cavities of the brain containing cerebrospinal fluid which nourishes and cleanses the brain.

Earlier studies from the lab were the first to show that ceramide is present in these fast-moving algae cilia where it has likely been at work for a billion years.  The group reasoned that algae, an old and simple plant, seemed a good first model to figure out what regulates cilia. Cilia in algae are comparatively big, about 10 times those in mammalian cells, so with just a regular microscope, the researchers could easily watch cilia movement. The current study showed that when they applied even a miniscule amount of a fungus toxin known to inhibit ceramide production, the usually agile algae stopped, the cilia shrank and some fell off.

The current study shows that one of the protein kinases that is highly conserved from Chlamydomonas to mammals and critical for ciliogenesis is glycogen synthase kinase-3 (GSK3). The lab explain that in Chlamydomonas an GSK3 isoform regulates flagellar length.  Results show that ceramide present in the cilia of human ependymal cells activates GSK3 to regulate cilia. The researchers conclude that in both algae and ependymal cells, the two can be found together and, without their teamwork, hydrocephalus, excess fluid on the brain, can result.

The team surmise that their findings suggest that if ceramide is one of the key regulators of cerebrospinal fluid movement, it may also be a drug target to help normalize the function of cilia.  For the future, the researchers plan to visualize cilia movement in ependymal cells.

Source: University of Georgia

 

Cilia labelled in ependymal cells with tubulin antibodies by indirect immunofluorescence. 1) Acetylated tubulin (cilia labelling)/ Alexa 488, 2) Détyrosinated tubulin (cilia labelling)/ Cy3, 3) Tyrosinated tubulin (cilia labelling in pseudo color magenta)/ Cy5, 4) Cell nuclei stained with Hoescht Courtesy of Dr Saoudi, GIN, Grenoble.

Cilia labelled in ependymal cells with tubulin antibodies by indirect immunofluorescence. 1) Acetylated tubulin (cilia labelling)/ Alexa 488, 2) Détyrosinated tubulin (cilia labelling)/ Cy3, 3) Tyrosinated tubulin (cilia labelling in pseudo color magenta)/ Cy5, 4) Cell nuclei stained with Hoescht Courtesy of Dr Saoudi, GIN, Grenoble.

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