Motor proteins carry valuable cargo into neurons. How can we control their movement?

BUFFALO, NY – Inside neurons, motor proteins carry valuable cargo, moving essential goods along threadlike routes called microtubule tracks.

This miniature highway system is vital for keeping neurons healthy: when traffic is flowing, critical materials can reach areas far from cells where they are needed. When the system breaks down, it can hamper cell function and lead to cell death.

Now scientists have identified a new tool for traffic control. In a study published in December 2021 in the journal Development, researchers describe how an enzyme called GSK3β can act as an off switch for a type of motor protein called kinesin 1.

“Our publication details how GSK3β attaches a molecular tag to kinesin 1 motors, causing the motors to shut down without detaching from the microtubule tracks. We are super excited because we now know how to control the ‘motor’ while ‘it’s moving on a track,’ says lead author Shermali Gunawardena, PhD, associate professor of biological sciences at the University at Buffalo College of Arts and Sciences.

“Cargo transport by motors is a tightly coordinated process, and yet the molecular mechanisms that control these ‘motors’ along microtubule pathways remain largely unknown,” says study first author Rupkatha Banerjee, PhD. postdoctoral research associate at Scripps Research. in Florida who completed her doctorate in biological sciences at UB.

“Our work provides an in-depth understanding of how the enzyme GSK3β acts as a key regulator of the kinesin 1 motor,” Banerjee adds. “Specifically, we have identified a specific site on kinesin 1 that is modified by GSK3β. Using molecular biology, in vitro analysis and fly genetics, combined with in vivo imaging techniques, we were able to unravel the mechanistic details by which disruption of this particular site affects motor movement and attachment. engine to microtubule cargoes or tracks in an entire organism. ”

The findings – based on laboratory experiments, including some in the neurons of fruit fly larvae – could open the door to future research into pause motors as a disease treatment mechanism.

Gunawardena points to cancer as a potential example: “In cancer, cells divide rapidly and motors are involved. So if you can stop the motors, you can impact this continued cell division,” she says.

From a different angle, she notes that, “in some neurodegenerative diseases, you see cargo blockages in neurons because things get stuck in the way. If we can control the motors and stop them, maybe we can help clear the way and remove these blockages. In some parts of California during rush hour you have traffic lights that only let a certain number of cars in at a certain time to prevent the freeway from getting too full which would slow traffic and would cause traffic blockages. Perhaps we can apply this concept to neurons as well, if we can control motors by turning them on or off.

The study’s co-authors also include Piyali Chakraborty, graduate of science in UB’s neuroscience program, and Michael C. Yu, PhD, associate professor of biological sciences at UB.

In addition to detailing how GSK3β can shut down kinesin 1 motors, research has explored other aspects of the enzyme’s interaction with motors, with results underscoring the idea that GSK3β plays an important role in the fine-tuning the motor movement of kinesin 1 in neurons inside a living organism. .

“This publication emphasizes fine-tuning of motor function as a potential approach to restoring transport defects that contribute to neurodegeneration and cancer,” says Banerjee.

The research was supported by the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health; the John R. Oishei Foundation; and the Mark Diamond Research Fund at UB.