Tata Institute of Fundamental Research
Dr. Koushika is a reader at Tata Institute of Fundamental Research, Mumbai, India.
Regulation of Organelle Transport in Axons
Traffic tie-ups and crazy drivers frustrate Sandhya Koushika as much as anyone. But instead of cursing congested roadways and erratic motorists, she studies them for insights that might apply to her research.
Koushika’s interest is axonal transport—the highly coordinated movement of molecular cargo from one end of a nerve cell to the other. It’s a process with many parallels to the comings and goings she observes on the road.
“Axonal transport is something like the transport of vegetables from the farm where they’re grown to the city where they’re used,” she says. In nerve cells, organelles such as presynaptic vesicles are “grown” in one part of the cell but must be transported down its length—up to one meter in humans—to a synapse at the end. There, neurotransmitters packaged in the vesicles are released to transmit signals from the nerve cell to a target cell across the synapse, the process through which we sense and respond to our environment.
“This transport is carried out with a multiplicity of molecular motors—you can think of them as little vehicles that have decisions to make: what to carry, where to drop it off, whether to return for another load or stay at the destination,” Koushika says. In a properly functioning nervous system, each decision is made correctly, and cargos are dropped off where and when they are needed. When the process isn’t properly controlled, however, neurodegenerative diseases are the result, such as amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) and Charcot–Marie–Tooth2A, an inherited condition that retards the transmission of nerve impulses in the feet and legs.
To understand the control of axonal transport, Koushika uses a variety of approaches, all carried out in the model organism Caenorhabditis elegans, a tiny, transparent worm. Through genetic screens, her lab identifies molecules and mechanisms that regulate various steps in the process. In one study, they found that a protein called UNC-16 is required for the correct cargo to attach to its molecular motor.
Genetic screens led to another finding that shattered assumptions about what happens to motors once they’ve delivered their cargo. “We thought maybe they would be used again to go back and pick up more cargo, but we found that, at least for one motor carrying presynaptic vesicles, that was not happening,” Koushika says. “The synaptic vesicle motor UNC-104 is used only once and disposed of.”
Taking advantage of the see-through nature of C. elegans, Koushika’s research group makes high-quality movies of axonal transport in living worms, an achievement that requires keeping the wiggly creatures still. Anesthesia is out—it interferes with axonal transport—so the researchers developed a simple and versatile technique to immobilize tiny worms and larvae within a microfluidic device that pins them down with gentle pressure.
“Live imaging allows us to ask questions about how things are moving and why they’re moving as they are, so that we’re not only identifying molecular players but also the processes in which they participate,” Koushika says. For instance, her group is investigating how cargo is routed in branched neurons when it encounters a fork.
Down the road, Koushika wants to investigate the transport of another type of cargo, mitochondria, which travel in the same direction as presynaptic vesicles. She also wants to learn about the transport of cellular debris and messages about the health of the neuron in the opposite direction—from synapse to cell body.
Like the molecular cargos she now studies, Koushika sensed from the outset where she was headed: straight toward a career in science. One incident from her childhood in Baroda, India, was pivotal.
“I used to read a lot, and my mom would leave me in a bookstore when she went shopping,” she says. “One day an old man in the store gave me Marie Curie’s biography. I was so completely moved by it. It was eye-opening to me that someone could be so passionate about finding out something and have the dedication to carry it through.”
With encouragement from her family and scientific mentors, she managed to translate her early curiosity into the same kind of passion and dedication. “I still have that very idealistic view of science,” she says. “It never really went away.”
Childhood memories, supportive family, stimulating colleagues—Koushika draws inspiration from many sources. All of those, and the occasional traffic jam.