Unlikely sea creature sheds light on brain disorders

Researchers at the Marine Biological Laboratory in Woods Hole study sea creatures to better understand life processes, which sometimes leads to scientific and medical breakthroughs. One scientist is studying how one such organism – the lamprey – may hold clues to why certain people fall prey to neurological diseases like Parkinson’s and Alzheimer’s.

Lampreys – eel-like parasitic fish that are among our earliest vertebrate relatives – possess a nervous system with amazing attributes. Unlike humans, they can regenerate their spinal cord if it is severed. Furthermore, lampreys possess comparatively huge axons, the long arm of the nerve cell or neuron used to transmit a signal to another cell. In humans, axons are a mere micron, or 0.000039 inches, in diameter, said Jennifer Morgan, Ph.D., an associate scientist at the Marine Biological Laboratory in Woods Hole, and director of its Eugene Bell Center for Regenerative Biology and Tissue Engineering. In lampreys, some of the axons measure 20-80 microns in diameter.

“Because they’re big, ….and also near the surface (of the spinal cord), they’re experimentally easy to access,” she said.

Lampreys’ large axons use the same neurotransmitter chemicals that human nerve cells do to communicate across a synapse – the microscopic gap between two nerve cells – thereby making them good animal subjects for study of synapses.

It is in the synapse that Morgan’s work focuses. She recently received a five-year, roughly $2.5 million grant from the National Institutes of Health to examine why a protein called alpha-synuclein accumulates in the brain synapses of people with Parkinson’s disease, Lewy body dementia and some forms of Alzheimer’s disease and how that affects synapse function.

According to Morgan, in normal neurons this protein apparently assists with recycling of synaptic vesicles – little packets in the cell that release neurotransmitters by fusing with the cell membrane and emptying their contents into the synapse during the transfer of a nerve impulse. But in these degenerative diseases, molecules of alpha-synuclein link together and form clumps at the synapse, and empty vesicles are not moved back inside the cell to be refilled with neurotransmitters, but rather get stuck in the synaptic membrane.

“The vesicles that contain the neurotransmitters go away,” Morgan said. “It happens very quickly and very acutely.”

The cells “run out of vesicles,” she continued, and neurotransmission stops.

Morgan said scientists had previously known that alpha-synuclein builds up in the body of diseased neurons, but more recently learned it also builds up in synapses.

“In Parkinson’s disease, you have a mutation in a gene for alpha-synuclein, and what happens is that over time, and in an age-related manner through a mechanism which we don’t yet understand, this alpha-synuclein protein will start to aggregate and build up in the neuron,” Morgan said. “And everyone was looking near the nucleus, in the cell body, the big part of the neuron, and you get these big aggregates of protein. And I thought that was kind of curious, because actually alpha-synuclein in its normal function is down at the synapse.”

“We don’t know its normal function quite as well as we’d like to now, but we do know that it’s involved in synaptic transmission,” she said of alpha-synuclein. “We don’t know as much about its normal function as we do about its pathological function.”

“In Lewy body dementia, up to 90 percent of the buildup of synuclein is in the synapse,” she said, and it may be an early indicator of disease. This buildup has also been discovered in the neurons of injured brains and spinal cords, she added. In a separate project, Morgan’s lab is also using the lamprey to study how restoration of neurotransmission might be possible after spinal injury, a feat the animals can accomplish.

The NIH grant extends the Bell Center’s basic research of alpha-synuclein.

“We know the impact of too much synuclein on the synapse; we want to understand that a little more mechanistically. So, exactly how is that happening, how is that working, and designing strategies for correcting it,” Morgan said.

The lab seeks to learn more about how aggregates of alpha-synuclein interfere with neurotransmission by using the protein isolated from human brains. Harvard researchers provided the protein, she said. Different variations of alpha-synuclein can be introduced into lamprey synapses and the effects studied.

“You’ve got this protein that functions normally in the cell. Then something happens. Maybe it gets misfolded, (starts) self-associating, which leads to aggregation,” Morgan said. “As part of that process, you’ve got one protein – one alpha-synuclein binding to another alpha-synuclein, and those two alpha-synuclein binding to another.

“What happens if we put in two alpha-synuclein molecules that are locked together?” she said. “What happens if you put in four alpha-synuclein stuck together? What happens if you put in 10 stuck together? Do they have the same phenotype? Are they progressively more toxic?”

Not Enough Known

Scientists do know enough to start devising ways to correct the problem of protein accumulation in the synapse, Morgan said.

While her lab’s work is not yet at the stage to talk to pharmaceutical companies about possible therapies, Gal Bitan, a researcher at the University of California Los Angeles, does hold a patent for an experimental drug to prevent self-association of alpha-synuclein in neurological diseases, she said. Morgan’s lab has a patent pending with Bitan for the same drug for application to spinal injuries. The drug, CLRO1, may also disrupt some viruses, including HIV and herpes simplex, according to the Bitan Laboratory at UCLA’s website.

The drug still has to undergo much pre-clinical testing, Morgan said.

“Certainly, when we put it in the animals for spinal cord injury, it was not toxic – the animals recovered,” Morgan said.

Drugs that work in the synapse have been around for years. For example, Paxil and Zoloft and other selective serotonin uptake inhibitors or SSRIs block the reabsorption of the neurotransmitter serotonin and are used to treat depression. Despite this, scientists still have much to learn about how synapses and the brain operate, Morgan said.

“The classic example is that lithium is the only thing that’s used to treat bipolar disease and nobody knows how that works, but it works,” she said.

Use of the lamprey axon gives Morgan and her colleagues an opportunity to discover more about how the nervous system operates at the molecular level.

“This is a really exciting example of how we can use a marine organism to address core biomedical problems that have some future impact on how we think about what’s happening in humans,” she said.