Prof. Li-Huei Tsai pinpoints the molecular culprits behind devastating brain disorders like a shrewd detective rounding up likely suspects. She recently made key discoveries that may enable new therapies for schizophrenia and Alzheimer’s disease.

The director of the Picower Institute for Learning and Memory, Tsai investigates a gene called DISC1 (Disrupted in Schizophrenia 1), which, when mutated, is strongly implicated in the psychiatric disorder for which it is named. With symptoms that include hallucinations, paranoia, and cognitive impairment, schizophrenia affects roughly 2.4 million American adults, making it the most common psychiatric disorder after depression.

Although several genetic factors likely play a role in this complex disease, DISC1 is “so far considered the most revealing candidate gene not just for schizophrenia but for a number of different psychiatric disorders, including bipolar disorder and major depression,” says Tsai.

She revealed that DISC1, found in high concentrations in the brain’s stem cells, is essential for both normal brain development in utero and growth of new neurons in the adult brain. When she and her colleagues reduced levels of the gene in adult mice, the animals’ brain cells failed to regenerate, and the mice displayed behaviors consistent with schizophrenia in humans.

In further tests, Tsai determined that DISC1 is part of the same signaling pathway targeted by lithium, a mood stabilizer commonly prescribed to people with bipolar disorder. While lithium has little effect on schizophrenics, evidence increasingly suggests that “at the genetic level, there is a great extent of overlap between schizophrenia and bipolar disorder,” says Tsai.

By elucidating the signaling pathway in which DISC1 functions, Tsai points the way toward other genes and molecules with possible links to schizophrenia and related psychiatric disorders.

“We want to have a better idea of how many of these genes converge on the signaling pathway, because I think the implication is going to be huge in terms of therapeutic intervention,” she says.

For more than a decade, Tsai has also probed possible mechanisms behind Alzheimer’s, the most common form of dementia in old age. She first witnessed the effects of dementia at the age of four, when she found herself guiding her grandmother home from the market after the woman suffered a sudden lapse of memory. Alzheimer’s affects 30 million people worldwide — a number that is expected to triple over the next few decades as human life spans increase.

Recently, Tsai singled out an enzyme called HDAC2 (histone deacetylase-2) as a barrier to learning and memory. This enzyme regulates the expression of a group of genes implicated in plasticity — the brain’s ability to change in response to experience — and memory formation. Tsai successfully used drugs called HDAC inhibitors to shut down HDAC2 in mice afflicted with an Alzheimer’s-like disease. The treatment helped restore the animals’ long-term memory and improve their ability to learn new tasks.

The mice with which Tsai experiments are themselves an innovation of her laboratory — one that has accelerated her own work and advanced the field of Alzheimer’s research as a whole. Tsai engineered the animals to experience Alzheimer’s symptoms much sooner than previously possible, thus enabling researchers to quickly test a wide variety of approaches to prevent, halt, and even reverse the ravages of dementia.

Tsai estimates that HDAC inhibitor-based drugs for Alzheimer’s patients — perhaps in combination with other drugs that prevent neurodegeneration — could enter clinical trials in as few as three to five years. She acknowledges that brain disorders present a dauntingly complex challenge, but that is part of what drives her. “The brain is fascinating. It’s the last frontier.”

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