The next time you drop into a pet store, pass by the puppies and head to the next frontier in genetics research: the fish department. There — see the blue ones with the gold stripes? Zebrafish. They are tenants of aquariums everywhere, so common most people don't even notice them. But to geneticists, danio rerio are the stars of a fascinating DNA drama.

"They are very interesting," says Su Guo, assistant professor of biopharmaceutical sciences and pharmaceutical chemistry at the UCSF School of Pharmacy. "As embryos, they are transparent: you can see every cell as it develops. The older fish are like little old people. Their scales don't look shiny anymore and they get all bent up."

Bent up or not, zebrafish may prove to be the best vertebrate models for research into the causes of Parkinson's disease, Alzheimer's disease, and related neurodegenerative disorders. But that's not all: A handful of labs, including Guo's, also are relying on zebrafish to suss out the molecular underpinnings of addiction and substance abuse.

The common thread to all these disparate research efforts: dopamine. In Parkinson's disease, the brain neurons that manufacture to this important neurotransmitter are destroyed when cellular proteins begin clumping together into aggregates called Lewy bodies. The primary ingredient of Lewy bodies is a protein called alpha-synuclein. Guo and her colleagues have created zebrafish that overexpress cellular alpha-synuclein, an important step toward understanding why this protein is toxic to dopamine neurons. Here's one possible scenario: According to recent research, alpha-synuclein forms proto-fibrils before coalescing into Lewy bodies. The proto-fibrils themselves may be responsible for the damage to dopamine neurons, while the Lewy bodies may be the product of some sort of protective cellular response. Growth of these proto-fibrils may require dopamine itself, which would explain the highly targeted nature of Parkinson's.

Is this the process leading to Parkinson's? To know for sure, scientists must have a vertebrate model of the disease whose genome is well understood — and there's where Guo's zebrafish come in. Sequencing of the zebrafish genome is well under way; scientists heading up the international effort expect to finish by the end of this year. Already it is clear that the zebrafish genome is at least 70 percent homologous to the human genome. If Guo can reproduce Parkinson's in these little fish, then the hunt for errant proteins and mutated DNA should move quickly. "If a Parkinson's model works in zebrafish, it would be a major breakthrough," says Guo. "It's what we're dreaming of. Once we have a model for Parkinson's disease in vertebrates, we will be able to find the genes involved in the disease process."

The work is important not just to Parkinson's patients. Several other neurological disorders are characterized by protein aggregation: Alzheimer's has its betaamyloid plaques, while Huntington's is distinguished by clumps of the mysterious huntingtin protein. A growing list of others, from Lou Gehrig's disease to retinitis pigmentosa, are now known to share this trait. In many, the aggregation seems to begin with a misfolding of proteins as they are manufactured, a finding that links these well-known neurodegenerative disorders directly to such exotic prion diseases as nv-CJD (new variant Creutzfeldt-Jakob disease), the human version of mad cow disease. So a well-understood vertebrate model for any of these conditions could be a godsend to neuroscientists working in many fields.

Including some you might not expect. Dopamine and its related circuitry also play a significant role in the biology of mental illness and addiction. (Many antipsychotic and antidepressant drugs, in fact, cause Parkinson's in a small number of patients taking them.) Cocaine creates a buzz in the brain partly by p reventing the reuptake of dopamine in the synapse — making it, in effect, a fuse that refuses to blow. Amphetamines work in much the same way. Biologists like Guo believe that there is a genetic explanation for why some people become addicted to these substances and some don't.

"Substance abuse used to be thought of as a social problem, just bad behavior," says Guo. "But studies show that genetics has a strong impact on addiction, and we know that dopamine is involved in establishing these preferences. One of our goals is to use zebrafish to find out what genes are responsible."

Her approach is a case study in forward genetics. In a series of complicated experiments, Guo and her colleagues have tracked larval zebrafish as they wander in and out of waters laced with morphine, alcohol and amphetamines. The goal is to phenotype the fish, to learn something about their individual preferences, and then to find genetic mutations underlying these behaviors. These mutations may be related to dopamine, or they may point Guo to entirely new regulatory systems.

All of which raises some unique research issues. How do you know when a fish likes morphine or hates alcohol? Heck, how do you know when a fish likes anything? As it turns out, zebrafish may not be so different from you and me. A few years back, Guo co-authored a paper on the effects of alcohol on her tiny subjects. Compared to their sober schoolmates, the team found, the inebriates were more aggressive, less sociable, and prone to zip around pointlessly near the surface of the tank. The title of the paper: "Drinks Like a Fish."

In early 2004, Guo's lab moves to UCSF Mission Bay's Genetics, Development and Behavioral Sciences building. "Many of us working in this area will all be in the same building for the first time," she says. "There will be a lot more potential for interaction." Fish aren't the only creatures who prefer to move forward together.

Source: Mike Mason

Last updated January 28, 2005

Su Guo

Su Guo. Photo by Majed.