Title

Genetic Studies of Microtubule Stability and Cellular Trafficking in the Nematode C. elegans

Presentation Type

Event

Start Date

27-4-2019 10:50 AM

End Date

27-4-2019 11:30 AM

Abstract

Microtubules (MTs) act as highways, and molecular motors act as cargo trucks in cells. The O’Hagan lab uses the roundworm C. elegans to study how glutamate side-chains added to MTs act as signposts to regulate the activity of motors and the structure of MTs in neurons. The CCPP-1 deglutamylase removes glutamylation and TTLL glutamylases add glutamylation to neuronal MTs. In humans, loss of these enzymes results in neurodegeneration, retinal dystrophy, and sperm immotility.

Because cilia from all eukaryotes share conserved MT ultrastructures and molecular motors, they can be used as a model to study how MT glutamylation regulates the cytoskeleton and motor transport. When the CCPP-1 deglutamylase is absent, ciliary MTs degenerate. Loss of glutamylase function can suppress this ciliary degeneration, suggesting that a balance of glutamylase and deglutamylase function is essential to regulate ciliary MTs. We are using genetic and ultrastructural methods to characterize mutations that suppress ciliary degeneration when CCPP-1 is lost.

We are also testing how MT glutamylation affects motor function in C. elegans neurons by observing fluorescently tagged motors using time-lapse epifluorescence microscopy. Additionally, we are exploring the how microtubule associated proteins, such as the Alzheimer’s disease protein Tau, genetically interact with MT glutamylation.

Our findings should help illuminate if glutamylation enzymes might provide novel drug targets for the amelioration of neurodegenerative disease and improved regeneration after neuronal injury.

Lastly, we are performing pilot genetic studies on a C. elegans homolog of rootletin, which like the CCPP-1 deglutamylase, is required for maintenance of ciliary MTs.

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Apr 27th, 10:50 AM Apr 27th, 11:30 AM

Genetic Studies of Microtubule Stability and Cellular Trafficking in the Nematode C. elegans

Microtubules (MTs) act as highways, and molecular motors act as cargo trucks in cells. The O’Hagan lab uses the roundworm C. elegans to study how glutamate side-chains added to MTs act as signposts to regulate the activity of motors and the structure of MTs in neurons. The CCPP-1 deglutamylase removes glutamylation and TTLL glutamylases add glutamylation to neuronal MTs. In humans, loss of these enzymes results in neurodegeneration, retinal dystrophy, and sperm immotility.

Because cilia from all eukaryotes share conserved MT ultrastructures and molecular motors, they can be used as a model to study how MT glutamylation regulates the cytoskeleton and motor transport. When the CCPP-1 deglutamylase is absent, ciliary MTs degenerate. Loss of glutamylase function can suppress this ciliary degeneration, suggesting that a balance of glutamylase and deglutamylase function is essential to regulate ciliary MTs. We are using genetic and ultrastructural methods to characterize mutations that suppress ciliary degeneration when CCPP-1 is lost.

We are also testing how MT glutamylation affects motor function in C. elegans neurons by observing fluorescently tagged motors using time-lapse epifluorescence microscopy. Additionally, we are exploring the how microtubule associated proteins, such as the Alzheimer’s disease protein Tau, genetically interact with MT glutamylation.

Our findings should help illuminate if glutamylation enzymes might provide novel drug targets for the amelioration of neurodegenerative disease and improved regeneration after neuronal injury.

Lastly, we are performing pilot genetic studies on a C. elegans homolog of rootletin, which like the CCPP-1 deglutamylase, is required for maintenance of ciliary MTs.